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1. 3′-Phosphoadenosine 5′-Phosphosulfate Allosterically Regulates Sulfotransferase Turnover

Author:
Wang Ting; Cook Ian; Leyh Thomas S.
Source:
Biochemistry 2014 v.53 no.44 pp. 6893-6900
ISSN:
1520-4995
Subject:
active sites; catalytic activity; drugs; humans; liver; primary amines; sulfotransferases
Abstract:
... Human cytosolic sulfotransferases (SULTs) regulate the activities of thousands of small moleculesmetabolites, drugs, and other xenobioticsvia the transfer of the sulfuryl moiety (-SO₃) from 3′-phosphoadenosine 5′-phosphosulfate (PAPS) to the hydroxyls and primary amines of acceptors. SULT1A1 is the most abundant SULT in liver and has the broadest substrate spectrum of any SULT. Here we present t ...
DOI:
10.1021/bi501120p
PubMed:
25314023
PubMed Central:
PMC4230322

2. ATP Acyl Phosphate Reactivity Reveals Native Conformations of Hsp90 Paralogs and Inhibitor Target Engagement

Author:
Nordin Brian E.; Liu Yongsheng; Aban Arwin; Brown Heidi E.; Wu Jiangyue; Hainley Anna K.; Rosenblum Jonathan S.; Nomanbhoy Tyzoon K.; Kozarich John W.
Source:
Biochemistry 2015 v.54 no.19 pp. 3024-3036
ISSN:
1520-4995
Subject:
adenosine triphosphate; adenosinetriphosphatase; drugs; humans; inhibitory concentration 50; phosphates; protein kinases; proteins
Abstract:
... Hsp90 is an ATP-dependent chaperone of widespread interest as a drug target. Here, using an LC-MS/MS chemoproteomics platform based on a lysine-reactive ATP acyl phosphate probe, several Hsp90 inhibitors were profiled in native cell lysates. Inhibitor specificities for all four human paralogs of Hsp90 were simultaneously monitored at their endogenous relative abundances. Equipotent inhibition of p ...
DOI:
10.1021/acs.biochem.5b00148

3. Abietane-Type Diterpenoids Inhibit Protein Tyrosine Phosphatases by Stabilizing an Inactive Enzyme Conformation

Author:
Michael K. Hjortness; Laura Riccardi; Akarawin Hongdusit; Sophia Ruppe; Mengxia Zhao; Edward Y. Kim; Peter H. Zwart; Banumathi Sankaran; Haribabu Arthanari; Marcelo C. Sousa; Marco De Vivo; Jerome M. Fox
Source:
Biochemistry 2018 v.57 no.40 pp. 5886-5896
ISSN:
1520-4995
Subject:
abietic acid; active sites; diterpenoids; drugs; human diseases; inhibitory concentration 50; insulin; molecular dynamics; nuclear magnetic resonance spectroscopy; protein-tyrosine-phosphatase; simulation models; therapeutics
Abstract:
... Protein tyrosine phosphatases (PTPs) contribute to a striking variety of human diseases, yet they remain vexingly difficult to inhibit with uncharged, cell-permeable molecules; no inhibitors of PTPs have been approved for clinical use. This study uses a broad set of biophysical analyses to evaluate the use of abietane-type diterpenoids, a biologically active class of phytometabolites with largely ...
DOI:
10.1021/acs.biochem.8b00655
PubMed:
30169954
PubMed Central:
PMC6219988

4. Alteration of the Flexible Loop in 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase Boosts Enthalpy-Driven Inhibition by Fosmidomycin

Author:
Kholodar Svetlana A.; Tombline Gregory; Liu Juan; Tan Zhesen; Allen C. Leigh; Gulick Andrew M.; Murkin Andrew S.
Source:
Biochemistry 2014 v.53 no.21 pp. 3423-3431
ISSN:
1520-4995
Subject:
Mycobacterium tuberculosis; X-ray diffraction; biosynthesis; calorimetry; crystal structure; deuterium; drugs; energy; enthalpy; fosmidomycin; humans; hydrogen bonding; isomerases; isoprenoids; isotopes; microorganisms; mutants; mutation; structure-activity relationships; titration
Abstract:
... 1-Deoxy-d-xylulose-5-phosphate reductoisomerase (DXR), which catalyzes the first committed step in the 2-C-methyl-d-erythritol 4-phosphate pathway of isoprenoid biosynthesis used by Mycobacterium tuberculosis and other infectious microorganisms, is absent in humans and therefore an attractive drug target. Fosmidomycin is a nanomolar inhibitor of DXR, but despite great efforts, few analogues with c ...
DOI:
10.1021/bi5004074
PubMed:
24825256
PubMed Central:
PMC4045324

5. Alternative Sigma Factor of Staphylococcus aureus Interacts with the Cognate Antisigma Factor Primarily Using Its Domain 3

Author:
Debabrata Sinha; Debasmita Sinha; Anindya Dutta; Tushar Chakraborty; Rajkrishna Mondal; Soham Seal; Asim Poddar; Subhrangsu Chatterjee; Subrata Sau
Source:
Biochemistry 2021 v.60 no.2 pp. 135-151
ISSN:
1520-4995
Subject:
DNA; DNA-directed RNA polymerase; Gram-positive bacteria; Staphylococcus aureus; binding capacity; dimerization; drugs; exhibitions; heat production; length; models; pathogenesis; protein-serine-threonine kinases; sigma factors; stoichiometry; stress response
Abstract:
... σᴮ, an alternative sigma factor, is usually employed to tackle the general stress response in Staphylococcus aureus and other Gram-positive bacteria. This protein, involved in S. aureus-mediated pathogenesis, is typically blocked by RsbW, an antisigma factor having serine kinase activity. σᴮ, a σ⁷⁰-like sigma factor, harbors three conserved domains designated σᴮ², σᴮ³, and σᴮ⁴. To better understan ...
DOI:
10.1021/acs.biochem.0c00881

6. The Amino-Acid Substituents of Dipeptide Substrates of Cathepsin C Can Determine the Rate-Limiting Steps of Catalysis

Author:
Rubach Jon K.; Cui Guanglei; Schneck Jessica L.; Taylor Amy N.; Zhao Baoguang; Smallwood Angela; Nevins Neysa; Wisnoski David; Thrall Sara H.; Meek Thomas D.
Source:
Biochemistry 2012 v.51 no.38 pp. 7551-7568
ISSN:
1520-4995
Subject:
acylation; amino acids; catalytic activity; cysteine proteinases; dipeptidyl-peptidase I; drugs; hydrolysis; isotopes; kinetics; models; molecular dynamics; solvents
Abstract:
... We examined the cathepsin C-catalyzed hydrolysis of dipeptide substrates of the form Yaa-Xaa-AMC, using steady-state and pre-steady-state kinetic methods. The substrates group into three kinetic profiles based upon the broad range observed for kcₐₜ/Kₐ and kcₐₜ values, pre-steady-state time courses, and solvent kinetic isotope effects (sKIEs). The dipeptide substrate Gly-Arg-AMC displayed large val ...
DOI:
10.1021/bi300719b

7. Analysis and Assay of Oseltamivir-Resistant Mutants of Influenza Neuraminidase via Direct Observation of Drug Unbinding and Rebinding in Simulation

Author:
Woods Christopher J.; Malaisree Maturos; Long Benjamin; McIntosh-Smith Simon; Mulholland Adrian J.
Source:
Biochemistry 2013 v.52 no.45 pp. 8150-8164
ISSN:
1520-4995
Subject:
binding sites; bound water; drug resistance; drugs; influenza; models; molecular dynamics; mutants; oseltamivir; public health; sialidase
Abstract:
... The emergence of influenza drug resistance is a major public health concern. The molecular basis of resistance to oseltamivir (Tamiflu) is investigated using a computational assay involving multiple 500 ns unrestrained molecular dynamics (MD) simulations of oseltamivir complexed with mutants of H1N1-2009 influenza neuraminidase. The simulations, accelerated using graphics processors (GPUs), and us ...
DOI:
10.1021/bi400754t

8. Analysis of Plasmodium vivax Chloroquine Resistance Transporter Mutant Isoforms

Author:
Hassett Matthew R.; Riegel Bryce E.; Callaghan Paul S.; Roepe Paul D.
Source:
Biochemistry 2017 v.56 no.41 pp. 5615-5622
ISSN:
1520-4995
Subject:
Plasmodium falciparum; Plasmodium vivax; biochemistry; chloroquine; drug resistance; drugs; humans; malaria; mutants; mutation; parasites; quantitative analysis; quinoline; vacuoles
Abstract:
... Chloroquine (CQ) resistance (CQR) in Plasmodium falciparum malaria is widespread and has limited the use of CQ in many regions of the globe. Malaria caused by the related human parasite P. vivax is as widespread as is P. falciparum malaria and has been treated with CQ as extensively as has P. falciparum, suggesting that P. vivax parasites have been selected with CQ as profoundly as have P. falcipa ...
DOI:
10.1021/acs.biochem.7b00749

9. Analysis of the Ability of Pramlintide To Inhibit Amyloid Formation by Human Islet Amyloid Polypeptide Reveals a Balance between Optimal Recognition and Reduced Amyloidogenicity

Author:
Wang Hui; Ridgway Zachary; Cao Ping; Ruzsicska Bela; Raleigh Daniel P.
Source:
Biochemistry 2015 v.54 no.44 pp. 6704-6711
ISSN:
1520-4995
Subject:
amyloid; death; drugs; glucose; humans; insulin replacement therapy; islets of Langerhans; mechanism of action; metabolism; noninsulin-dependent diabetes mellitus; polypeptides; rats
Abstract:
... The hormone human islet amyloid polypeptide (hIAPP or amylin) plays a role in glucose metabolism, but forms amyloid in the pancreas in type 2 diabetes (T2D) and is associated with β-cell death and dysfunction in the disease. Inhibitors of islet amyloid have therapeutic potential; however, there are no clinically approved inhibitors, and the mode of action of existing inhibitors is not well underst ...
DOI:
10.1021/acs.biochem.5b00567
PubMed:
26407043
PubMed Central:
PMC4656043

10. The Antiviral Drug Acyclovir Is a Slow-Binding Inhibitor of d-Amino Acid Oxidase

Author:
Katane Masumi; Matsuda Satsuki; Saitoh Yasuaki; Sekine Masae; Furuchi Takemitsu; Koyama Nobuhiro; Nakagome Izumi; Tomoda Hiroshi; Hirono Shuichi; Homma Hiroshi
Source:
Biochemistry 2013 v.52 no.33 pp. 5665-5674
ISSN:
1520-4995
Subject:
Herpesviridae infections; active sites; antiviral agents; bioactive properties; drugs; kinetics; models; serine; site-directed mutagenesis; structure-activity relationships; temperature
Abstract:
... d-Amino acid oxidase (DAO) is a degradative enzyme that is stereospecific for d-amino acids, including d-serine and d-alanine, which are believed to be coagonists of the N-methyl-d-aspartate (NMDA) receptor. To identify a new class of DAO inhibitor(s) that can be used to elucidate the molecular details of the active site environment of DAO, manifold biologically active compounds of microbial origi ...
DOI:
10.1021/bi400478a

11. Assay Development and Screening for the Identification of Ganglioside GM3 Synthase Inhibitors

Author:
Kenji Yamanaka; Yu Takahashi; Yuya Azuma; Yoshiji Hantani
Source:
Biochemistry 2020 v.59 no.12 pp. 1242-1251
ISSN:
1520-4995
Subject:
animal models; assays; chemotypes; drugs; gangliosides; glycosyltransferases; insulin receptors; insulin resistance; measurement; mice; noninsulin-dependent diabetes mellitus; patients; research; screening; solid phase extraction; spectrometers; therapeutics; tissues
Abstract:
... Ganglioside GM3 is a sialylated membrane-based glycosphingolipid that regulates insulin receptor signaling via direct association with the receptor. The level of expression of GM3 synthase (GM3S) and GM3 is increased in tissues of patients with diabetes and murine models of diabetes, and obesity-induced insulin resistance is attenuated in GM3S-deficient mice. Therefore, GM3S has been considered a ...
DOI:
10.1021/acs.biochem.0c00055

12. Assay and Inhibition of the Purified Catalytic Domain of Diacylglycerol Lipase Beta

Author:
Singh Praveen K.; Markwick Rachel; Lu Leanne; Howell Fiona V.; Williams Gareth; Doherty Patrick
Source:
Biochemistry 2016 v.55 no.19 pp. 2713-2721
ISSN:
1520-4995
Subject:
active sites; arachidonic acid; diacylglycerols; drugs; enzyme activity; enzyme inhibitors; glutathione transferase; lipoprotein lipase
Abstract:
... The diacylglycerol lipases (DAGLα and DAGLβ) hydrolyze DAG to generate 2-arachidonoylglycerol (2-AG), the principal endocannabinoid and main precursor of arachidonic acid (AA). The DAGLs make distinct tissue specific contributions toward 2-AG and AA levels, and therefore, selective modulators for these enzymes could play crucial roles toward harnessing their therapeutic potential. Relatively high- ...
DOI:
10.1021/acs.biochem.6b00221

13. Axial Hydrogen at C7 Position and Bumpy Tetracyclic Core Markedly Reduce Sterol’s Affinity to Amphotericin B in Membrane

Author:
Nakagawa Yasuo; Umegawa Yuichi; Nonomura Kenichi; Matsushita Naohiro; Takano Tetsuro; Tsuchikawa Hiroshi; Hanashima Shinya; Oishi Tohru; Matsumori Nobuaki; Murata Michio
Source:
Biochemistry 2015 v.54 no.2 pp. 303-312
ISSN:
1520-4995
Subject:
amphotericin B; cholesterol; drugs; ergosterol; fungi; hydrogen; mammals; molecular conformation; stable isotopes; toxicity; van der Waals forces
Abstract:
... The interaction of amphotericin B (AmB) with fungal ergosterol (Erg) is stronger than its interaction with mammalian cholesterol (Cho), and this property of AmB as an antifungal drug is thought to be responsible for its selective toxicity toward fungi. However, the mechanism by which AmB recognizes the structural differences between sterols, particularly minor difference in the sterol alicyclic po ...
DOI:
10.1021/bi5012942

14. BMS-708,163 Targets Presenilin and Lacks Notch-Sparing Activity

Author:
Crump Christina J.; Castro Suita V.; Wang Feng; Pozdnyakov Nikolay; Ballard T. Eric; Sisodia Sangram S.; Bales Kelly R.; Johnson Douglas S.; Li Yue-Ming
Source:
Biochemistry 2012 v.51 no.37 pp. 7209-7211
ISSN:
1520-4995
Subject:
Alzheimer disease; biochemistry; clinical trials; drugs; photoaffinity labeling
Abstract:
... The “Notch-sparing” γ-secretase inhibitor (GSI) BMS-708,163 (Avagacestat) is currently in phase II clinical trials for Alzheimer’s disease. Unlike previously failed GSIs, BMS-708,163 is considered to be a promising drug candidate because of its reported Notch-sparing activity for the inhibition of Aβ production over Notch cleavage. We now report that BMS-708,163 binds directly to the presenilin-1 ...
DOI:
10.1021/bi301137h
PubMed:
22931393
PubMed Central:
PMC3470910

15. BPEI-Induced Delocalization of PBP4 Potentiates β-Lactams against MRSA

Author:
Melissa A. Hill; Anh K. Lam; Patricia Reed; Madeline C. Harney; Beatrice A. Wilson; Erika L. Moen; Summer N. Wright; Mariana G. Pinho; Charles V. Rice
Source:
Biochemistry 2019 v.58 no.36 pp. 3813-3822
ISSN:
1520-4995
Subject:
bacteria; cell division; cell walls; developmental stages; drugs; enzyme activity; fluorescence microscopy; mechanism of action; methicillin-resistant Staphylococcus aureus; morbidity; mutation; polyethyleneimine; teichoic acids
Abstract:
... With its high morbidity rate and increasing resistance to treatment, methicillin-resistant Staphylococcus aureus (MRSA) is a grave concern in the medical field. In methicillin-susceptible strains, β-lactam antibiotics disable the penicillin binding proteins (PBPs) that cross-link the bacterial cell wall. However, methicillin-resistant strains have PBP2a and PBP4, which continue enzymatic activity ...
DOI:
10.1021/acs.biochem.9b00523
PubMed:
31429286
PubMed Central:
PMC6941424

16. Bacterial Model Membranes Reshape Fibrillation of a Functional Amyloid Protein

Author:
Ravit Malishev; Razan Abbasi; Raz Jelinek; Liraz Chai
Source:
Biochemistry 2018 v.57 no.35 pp. 5230-5238
ISSN:
1520-4995
Subject:
Bacillus subtilis; amyloid; anisotropy; biofilm; drugs; extracellular matrix; extracellular matrix proteins; fluorescence microscopy; models; nucleic acids; polysaccharides; protein content; soil bacteria; spectroscopy
Abstract:
... Biofilms are aggregates of cells that form surface-associated communities. The cells in biofilms are interconnected with an extracellular matrix, a network that is made mostly of polysaccharides, proteins, and sometimes nucleic acids. Some extracellular matrix proteins form fibers, termed functional amyloid or amyloid-like, to differentiate their constructive function from disease-related amyloid ...
DOI:
10.1021/acs.biochem.8b00002

17. Benzobisthiazoles Represent a Novel Scaffold for Kinase Inhibitors of CLK Family Members

Author:
Prak Krisna; Kriston-Vizi Janos; Chan A. W. Edith; Luft Christin; Costa Joana R.; Pengo Niccolo; Ketteler Robin
Source:
Biochemistry 2016 v.55 no.3 pp. 608-617
ISSN:
1520-4995
Subject:
drugs; etiology; models; neurodegenerative diseases; protein kinases; proteins; screening; viruses
Abstract:
... Protein kinases are essential regulators of most cellular processes and are involved in the etiology and progression of multiple diseases. The cdc2-like kinases (CLKs) have been linked to various neurodegenerative disorders, metabolic regulation, and virus infection, and the kinases have been recognized as potential drug targets. Here, we have developed a screening workflow for the identification ...
DOI:
10.1021/acs.biochem.5b01128
PubMed:
26701387
PubMed Central:
PMC4730229

18. Bimodal Actions of a Naphthyridone/Aminopiperidine-Based Antibacterial That Targets Gyrase and Topoisomerase IV

Author:
Elizabeth G. Gibson; Alexandria A. Oviatt; Monica Cacho; Keir C. Neuman; Pan F. Chan; Neil Osheroff
Source:
Biochemistry 2019 v.58 no.44 pp. 4447-4455
ISSN:
1520-4995
Subject:
Bacillus anthracis; DNA damage; Escherichia coli; Gram-negative bacteria; Mycobacterium tuberculosis; antibacterial properties; antibiotic resistance; catalytic activity; drugs; enzymes; fluoroquinolones; mechanism of action; mutation; single-stranded DNA; strains; topoisomerase inhibitors
Abstract:
... Gyrase and topoisomerase IV are the targets of fluoroquinolone antibacterials. However, the rise in antimicrobial resistance has undermined the clinical use of this important drug class. Therefore, it is critical to identify new agents that maintain activity against fluoroquinolone-resistant strains. One approach is to develop non-fluoroquinolone drugs that also target gyrase and topoisomerase IV ...
DOI:
10.1021/acs.biochem.9b00805

19. Binding of immunophilins to the 90 kDa heat shock protein (hsp90) via a tetratricopeptide repeat domain is a conserved protein interaction in plants

Author:
Owens-Grillo, J.K.; Stancato, L.F.; Hoffmann, K.; Pratt, W.B.; Krishna, P.
Source:
Biochemistry 1996 v.35 no.48 pp. 15249-15255
ISSN:
0006-2960
Subject:
antibodies; benzoquinones; drugs; heat shock proteins; humans; multiprotein complexes; protein folding; rabbits; radiolabeling; signal transduction; steroid receptors; wheat; wheat germ
Abstract:
... In animal cell lysates, multiprotein complexes containing hsp90, hsp70, p60, p23, and several immunophilins can assemble steroid receptors and oncogenic protein kineses, such as v-Src and v-Raf, into heterocomplexes that contain hsp90 and either immunophilins or, in the case of protein kineses, p50. The complexes with hsp90 are required for the proper functioning of these signal transduction syste ...
DOI:
10.1021/bi9615349
PubMed:
8952474

20. Biochemical Characterization and Structure-Based Mutational Analysis Provide Insight into the Binding and Mechanism of Action of Novel Aspartate Aminotransferase Inhibitors

Author:
Melissa C. Holt; Zahra Assar; Reza Beheshti Zavareh; Lin Lin; Justin Anglin; Oksana Mashadova; Daniel Haldar; Edouard Mullarky; Daniel M. Kremer; Lewis C. Cantley; Alec C. Kimmelman; Adam J. Stein; Luke L. Lairson; Costas A. Lyssiotis
Source:
Biochemistry 2018 v.57 no.47 pp. 6604-6614
ISSN:
1520-4995
Subject:
X-ray diffraction; aspartate transaminase; biochemical pathways; catalytic activity; computer simulation; drugs; enzyme inhibitors; homeostasis; mechanism of action; mutants; mutational analysis; neoplasm cells; oxidative stress; pancreatic neoplasms; pyridoxal phosphate; solubility; thermal stability
Abstract:
... Pancreatic cancer cells are characterized by deregulated metabolic programs that facilitate growth and resistance to oxidative stress. Among these programs, pancreatic cancers preferentially utilize a metabolic pathway through the enzyme aspartate aminotransferase 1 [also known as glutamate oxaloacetate transaminase 1 (GOT1)] to support cellular redox homeostasis. As such, small molecule inhibitor ...
DOI:
10.1021/acs.biochem.8b00914
PubMed:
30365304
PubMed Central:
PMC6487875

21. Biological and Structural Evaluation of 10R- and 10S-Methylthio-DDACTHF Reveals a New Role for Sulfur in Inhibition of Glycinamide Ribonucleotide Transformylase

Author:
Connelly Stephen; DeMartino Jessica K.; Boger Dale L.; Wilson Ian A.
Source:
Biochemistry 2013 v.52 no.30 pp. 5133-5144
ISSN:
1520-4995
Subject:
X-ray diffraction; biosynthesis; cell growth; diastereomers; drugs; folic acid; humans; hydrophilicity; hydrophobicity; inhibitory concentration 50; molecular models; mutants; neoplasm cells; sulfur; therapeutics
Abstract:
... Glycinamide ribonucleotide transformylase (GAR Tfase) is a folate-dependent enzyme in the de novo purine biosynthesis pathway, which has long been considered a potential target for development of anti-neoplastic therapeutics. Here we report the biological and X-ray crystallographic evaluations of both independent C10 diastereomers, 10S- and 10R-methylthio-DDACTHF, bound to human GAR Tfase, includi ...
DOI:
10.1021/bi4005182
PubMed:
23869564
PubMed Central:
PMC3823235

22. The CK1α Activator Pyrvinium Enhances the Catalytic Efficiency (kcₐₜ/Kₘ) of CK1α

Author:
Chen Shen; Bin Li; Luisana Astudillo; Murray P. Deutscher; Melanie H. Cobb; Anthony J. Capobianco; Ethan Lee; David J. Robbins
Source:
Biochemistry 2019 v.58 no.51 pp. 5102-5106
ISSN:
1520-4995
Subject:
alternative splicing; assays; catalytic activity; cells; degradation; drugs; exhibitions; non-specific serine/threonine protein kinase; phosphorylation; serine; threonine
Abstract:
... The serine/threonine protein kinase casein kinase 1α (CK1α) functions as a negative regulator of Wnt signaling, phosphorylating β-catenin at serine 45 (P–S45) to initiate its eventual ubiquitin-mediated degradation. We previously showed that the repurposed, FDA-approved anthelminthic drug pyrvinium potently inhibits Wnt signaling in vitro and in vivo. Moreover, we proposed that pyrvinium’s Wnt inh ...
DOI:
10.1021/acs.biochem.9b00891
PubMed:
31820934
PubMed Central:
PMC6942998

23. Calorimetric Studies of Ligands Binding to Glutathione S-Transferase from the Malarial Parasite Plasmodium falciparum

Author:
Quesada-Soriano Indalecio; Barón Carmen; García-Maroto Federico; Aguilera Ana M.; García-Fuentes Luís
Source:
Biochemistry 2013 v.52 no.11 pp. 1980-1989
ISSN:
1520-4995
Subject:
Plasmodium falciparum; antimalarials; calorimetry; dissociation; drugs; energy; gel chromatography; glutathione; glutathione transferase; ligands; parasites; protective effect; temperature; thermodynamics; titration
Abstract:
... Glutathione S-transferase, from the malarial parasite Plasmodium falciparum (PfGST), exerts a protective role in the organism and is thus considered an interesting target for antimalarial drug development. In contrast to other GSTs, it is present in solution as a tetramer and a dimer in equilibrium, which is induced by glutathione (GSH). These properties prevent a calorimetric titration from being ...
DOI:
10.1021/bi400007g

24. The Carbohydrate-Binding Site in Galectin-3 Is Preorganized To Recognize a Sugarlike Framework of Oxygens: Ultra-High-Resolution Structures and Water Dynamics

Author:
Saraboji Kadhirvel; Håkansson Maria; Genheden Samuel; Diehl Carl; Qvist Johan; Weininger Ulrich; Nilsson Ulf J.; Leffler Hakon; Ryde Ulf; Akke Mikael; Logan Derek T.
Source:
Biochemistry 2012 v.51 no.1 pp. 296-306
ISSN:
1520-4995
Subject:
ambient temperature; binding sites; calorimetry; carbohydrate binding; crystal structure; crystallography; deuterium; drugs; glycerol; lactose; ligands; molecular dynamics; nuclear magnetic resonance spectroscopy; oxygen; proteins; screening; titration
Abstract:
... The recognition of carbohydrates by proteins is a fundamental aspect of communication within and between living cells. Understanding the molecular basis of carbohydrate–protein interactions is a prerequisite for the rational design of synthetic ligands. Here we report the high- to ultra-high-resolution crystal structures of the carbohydrate recognition domain of galectin-3 (Gal3C) in the ligand-fr ...
DOI:
10.1021/bi201459p
PubMed:
22111949
PubMed Central:
PMC3255464

25. The Carboxyl Terminus of Eremomycin Facilitates Binding to the Non-d-Ala-d-Ala Segment of the Peptidoglycan Pentapeptide Stem

Author:
Chang James; Zhou Hongyu; Preobrazhenskaya Maria; Tao Peng; Kim Sung Joon
Source:
Biochemistry 2016 v.55 no.24 pp. 3383-3391
ISSN:
1520-4995
Subject:
Gram-positive bacteria; Staphylococcus aureus; alanine; antibiotics; binding sites; biosynthesis; cell walls; drugs; glycopeptides; nitrogen; nuclear magnetic resonance spectroscopy; peptidoglycans; stable isotopes
Abstract:
... Glycopeptide antibiotics inhibit cell wall biosynthesis in Gram-positive bacteria by targeting the peptidoglycan (PG) pentapeptide stem structure (l-Ala-d-iso-Gln-l-Lys-d-Ala-d-Ala). Structures of the glycopeptide complexed with a PG stem mimic have shown that the d-Ala-d-Ala segment is the primary drug binding site; however, biochemical evidence suggests that the glycopeptide–PG interaction invol ...
DOI:
10.1021/acs.biochem.6b00188
PubMed:
27243469
PubMed Central:
PMC6020039

26. Catalytic Mechanism of Cruzain from Trypanosoma cruzi As Determined from Solvent Kinetic Isotope Effects of Steady-State and Pre-Steady-State Kinetics

Author:
Xiang Zhai; Thomas D. Meek
Source:
Biochemistry 2018 v.57 no.22 pp. 3176-3190
ISSN:
1520-4995
Subject:
Chagas disease; Trypanosoma cruzi; catalytic activity; cruzipain; cysteine; drugs; histidine; isotopes; solvents; temperature
Abstract:
... Cruzain, an important drug target for Chagas disease, is a member of clan CA of the cysteine proteases. Understanding the catalytic mechanism of cruzain is vital to the design of new inhibitors. To this end, we have determined pH–rate profiles for substrates and affinity agents and solvent kinetic isotope effects in pre-steady-state and steady-state modes using three substrates: Cbz-Phe-Arg-AMC, C ...
DOI:
10.1021/acs.biochem.7b01250

27. Catalytic Transitions in the Human MDR1 P-Glycoprotein Drug Binding Sites

Author:
Wise John G.
Source:
Biochemistry 2012 v.51 no.25 pp. 5125-5141
ISSN:
1520-4995
Subject:
P-glycoproteins; adenosine triphosphate; binding sites; crystal structure; cytoplasm; drugs; extracellular space; humans; hydrolysis; ligands; molecular dynamics; multiple drug resistance; neoplasms
Abstract:
... Multidrug resistance proteins that belong to the ATP-binding cassette family like the human P-glycoprotein (ABCB1 or Pgp) are responsible for many failed cancer and antiviral chemotherapies because these membrane transporters remove the chemotherapeutics from the targeted cells. Understanding the details of the catalytic mechanism of Pgp is therefore critical to the development of inhibitors that ...
DOI:
10.1021/bi300299z
PubMed:
22647192
PubMed Central:
PMC3383123

28. Caught before Released: Structural Mapping of the Reaction Trajectory for the Sofosbuvir Activating Enzyme, Human Histidine Triad Nucleotide Binding Protein 1 (hHint1)

Author:
Rachit Shah; Kimberly M. Maize; Xin Zhou; Barry C. Finzel; Carston R. Wagner
Source:
Biochemistry 2017 v.56 no.28 pp. 3559-3570
ISSN:
1520-4995
Subject:
Lewis bases; active sites; binding proteins; catalytic activity; crystallography; drugs; enzyme substrates; enzymes; hepatitis C; histidine; humans; hydrolysis; nucleosides; protons
Abstract:
... Human histidine triad nucleotide binding protein 1 (hHint1) is classified as an efficient nucleoside phosphoramidase and acyl-adenosine monophosphate hydrolase. Human Hint1 has been shown to be essential for the metabolic activation of nucleotide antiviral pronucleotides (i.e., proTides), such as the FDA approved hepatitis C drug, sofosbuvir. The active site of hHint1 comprises an ensemble of stri ...
DOI:
10.1021/acs.biochem.7b00148

29. Characterization and Modeling of the Oligomeric State and Ligand Binding Behavior of Purified Translocator Protein 18 kDa from Rhodobacter sphaeroides

Author:
Li Fei; Xia Yan; Meiler Jens; Ferguson-Miller Shelagh
Source:
Biochemistry 2013 v.52 no.34 pp. 5884-5899
ISSN:
1520-4995
Subject:
Rhodobacter sphaeroides; apoptosis; benzodiazepines; bioactive properties; cholesterol; cryo-electron microscopy; curcumin; drugs; fluorescence; gossypol; inflammation; ligands; mammals; mitochondrial membrane; models; mutants; neoplasms; outer membrane proteins; porphyrins; retinoic acid; tryptophan
Abstract:
... Translocator Protein 18 kDa (TSPO), previously known as the peripheral-type benzodiazepine receptor (PBR), is a mitochondrial outer membrane protein that has been identified as a key player in cholesterol and porphyrin transport, apoptotic signaling, and cancer development, as well as neurological inflammation and disease. Despite a number of TSPO ligands whose effects have been studied with respe ...
DOI:
10.1021/bi400431t
PubMed:
23952237
PubMed Central:
PMC3756528

30. Characterization of Tetrahydrolipstatin and Stereoderivatives on the Inhibition of Essential Mycobacterium tuberculosis Lipid Esterases

Author:
Christopher M. Goins; Thanuja D. Sudasinghe; Xiaofan Liu; Yanping Wang; George A. O’Doherty; Donald R. Ronning
Source:
Biochemistry 2018 v.57 no.16 pp. 2383-2393
ISSN:
1520-4995
Subject:
Mycobacterium bovis; Mycobacterium tuberculosis; antigens; chemical bonding; crystal structure; drugs; enzyme inhibition; esterases; hydrolysis; lipids; phospholipases; polyketide synthases; stereochemistry; transferases
Abstract:
... Tetrahydrolipstatin (THL) is a covalent inhibitor of many serine esterases. In mycobacteria, THL has been found to covalently react with 261 lipid esterases upon treatment of Mycobacterium bovis cell lysate. However, the covalent adduct is considered unstable in some cases because of the hydrolysis of the enzyme-linked THL adduct resulting in catalytic turnover. In this study, a library of THL ste ...
DOI:
10.1021/acs.biochem.8b00152
PubMed:
29601187
PubMed Central:
PMC6128263

31. Characterization of the Photophysical, Thermodynamic, and Structural Properties of the Terbium(III)–DREAM Complex

Author:
Gonzalez Walter G.; Ramos Victoria; Diaz Maurizio; Garabedian Alyssa; Molano-Arevalo Juan Camilo; Fernandez-Lima Francisco; Miksovska Jaroslava
Source:
Biochemistry 2016 v.55 no.12 pp. 1873-1886
ISSN:
1520-4995
Subject:
Alzheimer disease; DNA; binding properties; bioactive properties; calcium; calmodulin; calorimetry; circular dichroism spectroscopy; dimerization; drugs; energy transfer; fluorescence; hydrophobicity; neurons; nuclear magnetic resonance spectroscopy; potassium channels; protein structure; signal transduction; terbium; thermodynamics; transcription factors
Abstract:
... DREAM (also known as K⁺ channel interacting protein 3 and calsenilin) is a calcium binding protein and an active modulator of KV4 channels in neuronal cells as well as a novel Ca²⁺-regulated transcriptional modulator. DREAM has also been associated with the regulation of Alzheimer’s disease through the prevention of presenilin-2 fragmentation. Many interactions of DREAM with its binding partners ( ...
DOI:
10.1021/acs.biochem.6b00067
PubMed:
26901070
PubMed Central:
PMC4867112

32. Chemical Editing of Macrocyclic Natural Products and Kinetic Profiling Reveal Slow, Tight-Binding Histone Deacetylase Inhibitors with Picomolar Affinities

Author:
Kitir Betül; Maolanon Alex R.; Ohm Ragnhild G.; Colaço Ana R.; Fristrup Peter; Madsen Andreas S.; Olsen Christian A.
Source:
Biochemistry 2017 v.56 no.38 pp. 5134-5146
ISSN:
1520-4995
Subject:
binding capacity; chemical elements; drugs; epigenetics; histone deacetylase; medicine; metabolism; neoplasms; synthesis
Abstract:
... Histone deacetylases (HDACs) are validated targets for treatment of certain cancer types and play numerous regulatory roles in biology, ranging from epigenetics to metabolism. Small molecules are highly important as tool compounds for probing these mechanisms as well as for the development of new medicines. Therefore, detailed mechanistic information and precise characterization of the chemical pr ...
DOI:
10.1021/acs.biochem.7b00725

33. Chemical Inhibitors of Epigenetic Methyllysine Reader Proteins

Author:
Milosevich Natalia; Hof Fraser
Source:
Biochemistry 2016 v.55 no.11 pp. 1570-1583
ISSN:
1520-4995
Subject:
carcinogenesis; cell cycle; chemical inhibitors; drugs; epigenetics; methylation; post-translational modification; proteins; stress response; viability
Abstract:
... Protein methylation is a common post-translational modification with diverse biological functions. Methyllysine reader proteins are increasingly a focus of epigenetics research and play important roles in regulating many cellular processes. These reader proteins are vital players in development, cell cycle regulation, stress responses, oncogenesis, and other disease pathways. The recent emergence ...
DOI:
10.1021/acs.biochem.5b01073

34. Chimeric hERG Channels Containing a Tetramerization Domain are Functional and Stable

Author:
Hausammann Georg J.; Grütter Markus G.
Source:
Biochemistry 2013 v.52 no.51 pp. 9237-9245
ISSN:
1520-4995
Subject:
Scorpiones; Xenopus laevis; cytoplasm; detergents; drugs; genes; humans; mutation; oocytes; potassium channels; solubilization
Abstract:
... Biochemical and detailed structural information of human ether-a-go-go-related gene (hERG) potassium channels are scarce but are a prerequisite to understand the unwanted interactions of hERG with drugs and the effect of mutations that lead to long QT syndrome. Despite the huge interest in hERG, to our knowledge, procedures that provide a purified, functional, and tetrameric hERG channel are not a ...
DOI:
10.1021/bi401100a

35. Cholesterol Asymmetrically Modulates the Conformational Ensemble of the Nucleotide-Binding Domains of P-Glycoprotein in Lipid Nanodiscs

Author:
Amanda F. Clouser; Yasmine H. Alam; William M. Atkins
Source:
Biochemistry 2020 v.60 no.1 pp. 85-94
ISSN:
1520-4995
Subject:
P-glycoproteins; behavior; cells; cholesterol; deuterium; drugs; environment; hydrolysis; kinetics; landscapes; lipid composition; mass spectrometry; toxins
Abstract:
... P-Glycoprotein (P-gp) is an ATP-dependent efflux pump that clears a wide variety of drugs and toxins from cells. P-gp undergoes large-scale structural changes and demonstrates conformational heterogeneity even within a single catalytic or drug-bound state, although the role of heterogeneity remains unclear. P-gp is found in a variety of cell types that vary in lipid composition, which modulates it ...
DOI:
10.1021/acs.biochem.0c00824

36. The Colicin E1 TolC-Binding Conformer: Pillar or Pore Function of TolC in Colicin Import?

Author:
Zakharov Stanislav D.; Wang Xin S.; Cramer William A.
Source:
Biochemistry 2016 v.55 no.36 pp. 5084-5094
ISSN:
1520-4995
Subject:
circular dichroism spectroscopy; colicins; cytotoxins; drugs; imports; ion channels; models; peptides; protein transport; thermal stability
Abstract:
... The mechanism by which the drug export protein TolC is utilized for import of the cytotoxin colicin E1 across the outer membrane and periplasmic space is addressed. Studies of the initial binding of colicin E1 with TolC, occlusion of membrane-incorporated TolC ion channels, and the structure underlying the colicin–TolC complex were based on the interactions with TolC of individual colicin transloc ...
DOI:
10.1021/acs.biochem.6b00621
PubMed:
27536862
PubMed Central:
PMC5366289

37. Combined Quantum Mechanics/Molecular Mechanics (QM/MM) Methods in Computational Enzymology

Author:
van der Kamp Marc W.; Mulholland Adrian J.
Source:
Biochemistry 2013 v.52 no.16 pp. 2708-2728
ISSN:
1520-4995
Subject:
active sites; application methods; catalysts; drugs; enzymatic reactions; enzymology; models; molecular dynamics; mutagenesis; prediction; quantum mechanics
Abstract:
... Computational enzymology is a rapidly maturing field that is increasingly integral to understanding mechanisms of enzyme-catalyzed reactions and their practical applications. Combined quantum mechanics/molecular mechanics (QM/MM) methods are important in this field. By treating the reacting species with a quantum mechanical method (i.e., a method that calculates the electronic structure of the act ...
DOI:
10.1021/bi400215w

38. Comparison of the Kinase Profile of Midostaurin (Rydapt) with That of Its Predominant Metabolites and the Potential Relevance of Some Newly Identified Targets to Leukemia Therapy

Author:
Paul W. Manley; Giorgio Caravatti; Pascal Furet; Johannes Roesel; Phi Tran; Trixie Wagner; Markus Wartmann
Source:
Biochemistry 2018 v.57 no.38 pp. 5576-5590
ISSN:
1520-4995
Subject:
drug toxicity; drugs; enzyme activity; enzyme inhibitors; metabolites; mutants; myeloid leukemia; patients; pharmacodynamics; radiometry; signal transduction; therapeutics; vascular endothelial growth factor receptor-2
Abstract:
... The multitargeted protein kinase inhibitor midostaurin is approved for the treatment of both newly diagnosed FLT3-mutated acute myeloid leukemia (AML) and KIT-driven advanced systemic mastocytosis. AML is a heterogeneous malignancy, and investigational drugs targeting FLT3 have shown disparate effects in patients with FLT3-mutated AML, probably as a result of their inhibiting different targets and ...
DOI:
10.1021/acs.biochem.8b00727

39. Computational and Experimental Characterization of Patient Derived Mutations Reveal an Unusual Mode of Regulatory Spine Assembly and Drug Sensitivity in EGFR Kinase

Author:
Ruan Zheng; Katiyar Samiksha; Kannan Natarajan
Source:
Biochemistry 2017 v.56 no.1 pp. 22-32
ISSN:
1520-4995
Subject:
Gibbs free energy; amino acids; drugs; hydrogen bonding; hydrophobicity; ligands; molecular dynamics; molecular models; mutants; mutation; mutational analysis; neoplasms; patients; protein kinases
Abstract:
... The catalytic activation of protein kinases requires precise positioning of key conserved catalytic and regulatory motifs in the kinase core. The Regulatory Spine (RS) is one such structural motif that is dynamically assembled upon kinase activation. The RS is also a mutational hotspot in cancers; however, the mechanisms by which cancer mutations impact RS assembly and kinase activity are not full ...
DOI:
10.1021/acs.biochem.6b00572
PubMed:
27936599
PubMed Central:
PMC5508873

40. Concurrent Cooperativity and Substrate Inhibition in the Epoxidation of Carbamazepine by Cytochrome P450 3A4 Active Site Mutants Inspired by Molecular Dynamics Simulations

Author:
Müller Christian S.; Knehans Tim; Davydov Dmitri R.; Bounds Patricia L.; von Mandach Ursula; Halpert James R.; Caflisch Amedeo; Koppenol Willem H.
Source:
Biochemistry 2015 v.54 no.3 pp. 711-721
ISSN:
1520-4995
Subject:
active sites; cytochrome P-450; drugs; equations; humans; metabolism; models; molecular dynamics; mutants
Abstract:
... Cytochrome P450 3A4 (CYP3A4) is the major human P450 responsible for the metabolism of carbamazepine (CBZ). To explore the mechanisms of interactions of CYP3A4 with this anticonvulsive drug, we carried out multiple molecular dynamics (MD) simulations, starting with the complex of CYP3A4 manually docked with CBZ. On the basis of these simulations, we engineered CYP3A4 mutants I369F, I369L, A370V, a ...
DOI:
10.1021/bi5011656
PubMed:
25545162
PubMed Central:
PMC4310618

41. Conformational Entropy of FK506 Binding to FKBP12 Determined by Nuclear Magnetic Resonance Relaxation and Molecular Dynamics Simulations

Author:
Gleb Solomentsev; Carl Diehl; Mikael Akke
Source:
Biochemistry 2018 v.57 no.9 pp. 1451-1461
ISSN:
1520-4995
Subject:
Gibbs free energy; binding proteins; binding sites; calorimetry; deuterium; drug interactions; drugs; entropy; ligands; molecular dynamics; nitrogen; nuclear magnetic resonance spectroscopy; simulation models; stable isotopes; titration
Abstract:
... FKBP12 (FK506 binding protein 12 kDa) is an important drug target. Nuclear magnetic resonance (NMR) order parameters, describing amplitudes of motion on the pico- to nanosecond time scale, can provide estimates of changes in conformational entropy upon ligand binding. Here we report backbone and methyl-axis order parameters of the apo and FK506-bound forms of FKBP12, based on ¹⁵N and ²H NMR relaxa ...
DOI:
10.1021/acs.biochem.7b01256

42. Conformational Features of Tau Fibrils from Alzheimer’s Disease Brain Are Faithfully Propagated by Unmodified Recombinant Protein

Author:
Morozova Olga A.; March Zachary M.; Robinson Anne S.; Colby David W.
Source:
Biochemistry 2013 v.52 no.40 pp. 6960-6967
ISSN:
1520-4995
Subject:
Alzheimer disease; amyloid; brain; circular dichroism spectroscopy; denaturation; drugs; electron microscopy; heparin; models; neurodegenerative diseases; periodicity; phosphorylation; post-translational modification; recombinant proteins; screening; seeds
Abstract:
... Fibrils composed of tau protein are a pathological hallmark of several neurodegenerative disorders including Alzheimer’s disease (AD). Here we show that when recombinant tau protein is seeded with paired helical filaments (PHFs) isolated from AD brain, the amyloid formed shares many of the structural features of AD PHFs. In contrast, tau amyloids formed with heparin as an inducing agenta common b ...
DOI:
10.1021/bi400866w
PubMed:
24033133
PubMed Central:
PMC4142060

43. Conformational Plasticity of the NNRTI-Binding Pocket in HIV-1 Reverse Transcriptase: A Fluorine Nuclear Magnetic Resonance Study

Author:
Sharaf Naima G.; Ishima Rieko; Gronenborn Angela M.
Source:
Biochemistry 2016 v.55 no.28 pp. 3864-3873
ISSN:
1520-4995
Subject:
HIV infections; Human immunodeficiency virus 1; RNA-directed DNA polymerase; active sites; drug resistance; drugs; fluorine; hydrophobicity; mutants; nuclear magnetic resonance spectroscopy; proteins
Abstract:
... HIV-1 reverse transcriptase (RT) is a major drug target in the treatment of HIV-1 infection. RT inhibitors currently in use include non-nucleoside, allosteric RT inhibitors (NNRTIs), which bind to a hydrophobic pocket, distinct from the enzyme’s active site. We investigated RT–NNRTI interactions by solution ¹⁹F nuclear magnetic resonance (NMR), using singly ¹⁹F-labeled RT proteins. Comparison of ¹ ...
DOI:
10.1021/acs.biochem.6b00113
PubMed:
27163463
PubMed Central:
PMC4955860

44. Conserved Hydrogen Bonding Networks of MitoNEET Tune Fe-S Cluster Binding and Structural Stability

Author:
Bak Daniel W.; Elliott Sean J.
Source:
Biochemistry 2013 v.52 no.27 pp. 4687-4696
ISSN:
1520-4995
Subject:
cysteine; drugs; electron transfer; humans; hydrogen bonding; iron; models; mutation; oxidation; protein structure; proteins; redox potential; sulfur
Abstract:
... While its biological function remains unclear, the three-cysteine, one-histidine ligated human [2Fe-2S] cluster containing protein mitoNEET is of interest because of its interaction with the anti-diabetes drug pioglitazone. The mitoNEET [2Fe-2S] cluster demonstrates proton-coupled electron transfer (PCET) and marked cluster instability, which have both been linked to the single His ligand. Highly ...
DOI:
10.1021/bi400540m
PubMed:
23758282
PubMed Central:
PMC3940166

45. Construction of a Part of a 3-Hydroxypropionate Cycle for Heterologous Polyketide Biosynthesis in Escherichia coli

Author:
Yuzawa Satoshi; Chiba Naoki; Katz Leonard; Keasling Jay D.
Source:
Biochemistry 2012 v.51 no.49 pp. 9779-9781
ISSN:
1520-4995
Subject:
Escherichia coli; acetyl coenzyme A; antibiotics; biosynthesis; carbon; chemical structure; drugs; methylmalonyl-coenzyme A; polyketide synthases; polyketides
Abstract:
... Polyketides, an important class of natural products with complex chemical structures, are widely used as antibiotics and other pharmaceutical agents. A clear barrier to heterologous polyketide biosynthesis in Escherichia coli is the lack of (2S)-methylmalonyl-CoA, a common substrate of multimodular polyketide synthases. Here we report a route for synthesizing (2S)-methylmalonyl-CoA from malonyl-Co ...
DOI:
10.1021/bi301414q

46. Contributions of Unique Active Site Residues of Eukaryotic UDP-Galactopyranose Mutases to Substrate Recognition and Active Site Dynamics

Author:
Da Fonseca Isabel; Qureshi Insaf A.; Mehra-Chaudhary Ritcha; Kizjakina Karina; Tanner John J.; Sobrado Pablo
Source:
Biochemistry 2014 v.53 no.49 pp. 7794-7804
ISSN:
1520-4995
Subject:
Aspergillus fumigatus; Mycobacterium tuberculosis; Trypanosoma cruzi; active sites; catalytic activity; cell walls; crystal structure; drugs; enzyme activation; enzyme kinetics; enzymes; fungi; humans; mutagenesis; mutants; parasites; uridine; uridine diphosphate; virulence
Abstract:
... UDP-galactopyranose mutase (UGM) catalyzes the interconversion between UDP-galactopyranose and UDP-galactofuranose. Absent in humans, galactofuranose is found in bacterial and fungal cell walls and is a cell surface virulence factor in protozoan parasites. For these reasons, UGMs are targets for drug discovery. Here, we report a mutagenesis and structural study of the UGMs from Aspergillus fumigat ...
DOI:
10.1021/bi501008z
PubMed:
25412209
PubMed Central:
PMC4270374

47. Cooperative Stabilization of Transthyretin by Clusterin and Diflunisal

Author:
Greene Michael J.; Klimtchuk Elena S.; Seldin David C.; Berk John L.; Connors Lawreen H.
Source:
Biochemistry 2015 v.54 no.2 pp. 268-278
ISSN:
1520-4995
Subject:
amyloid; amyloidosis; circular dichroism spectroscopy; dissociation; drugs; hydrophobicity; oligomerization; patients; point mutation; prealbumin; surface plasmon resonance
Abstract:
... The circulating protein transthyretin (TTR) can unfold, oligomerize, and form highly structured amyloid fibrils that are deposited in tissues, causing organ damage and disease. This pathogenic process is caused by a heritable TTR point mutation in cases of familial TTR-related amyloidosis or wild-type TTR in cases of age-associated amyloidosis (previously called senile systemic amyloidosis). The T ...
DOI:
10.1021/bi5011249
PubMed:
25478940
PubMed Central:
PMC4303310

48. Coordinated Regulation of β-Tubulin Isotypes and Epithelial-to-Mesenchymal Transition Protein ZEB1 in Breast Cancer Cells

Author:
Lobert Sharon; Graichen Mary E.; Morris Kevin
Source:
Biochemistry 2013 v.52 no.32 pp. 5482-5490
ISSN:
1520-4995
Subject:
animal ovaries; biomarkers; breast neoplasms; cell culture; cell viability; drug resistance; drug therapy; drugs; gene expression regulation; genes; messenger RNA; microRNA; models; neoplasm cells; ovarian neoplasms; paclitaxel; patients; taxanes; tubulin
Abstract:
... The regulation of β-tubulin isotypes, the primary targets for antimitotic chemotherapeutic drugs like taxanes, has implications for drug response and drug resistance. Over the past 15 years, micro-RNAs have been studied widely as regulators of mRNA levels. For example, the tumor suppressor miR-200c was shown in cell culture to target mesenchymal genes, including ZEB1 [Cochrane (2009) Mol. Cancer T ...
DOI:
10.1021/bi400340g

49. Correlation between AcrB Trimer Association Affinity and Efflux Activity

Author:
Ye Cui; Wang Zhaoshuai; Lu Wei; Zhong Meng; Chai Qian; Wei Yinan
Source:
Biochemistry 2014 v.53 no.23 pp. 3738-3746
ISSN:
1520-4995
Subject:
Escherichia coli; bioactive properties; detergents; drugs; ethidium; membrane proteins; micelles; mutants; mutation; oligomerization; polyacrylamide gel electrophoresis
Abstract:
... The majority of membrane proteins function as oligomers. However, it remains largely unclear how the oligomer stability of protein complexes correlates with their function. Understanding the relationship between oligomer stability and activity is essential to protein research and to virtually all cellular processes that depend on the function of protein complexes. Proteins make lasting or transien ...
DOI:
10.1021/bi5000838
PubMed:
24854514
PubMed Central:
PMC4067148

50. Correspondence of Fatty Acid and Drug Binding Sites on Human Serum Albumin: A Two-Dimensional Nuclear Magnetic Resonance Study

Author:
Krenzel Eileen S.; Chen Zhongjing; Hamilton James A.
Source:
Biochemistry 2013 v.52 no.9 pp. 1559-1567
ISSN:
1520-4995
Subject:
binding sites; crystal structure; dissociation; drugs; fatty acids; human serum albumin; nuclear magnetic resonance spectroscopy; spectral analysis; stable isotopes
Abstract:
... The ability of human serum albumin (HSA) to bind fatty acids (FA) in multiple sites has been revealed by many studies. Here we detect and characterize nine individual binding sites by two-dimensional (2D) nuclear magnetic resonance (NMR) spectroscopy of 18-[¹³C]-oleic acid (OA) complexed with HSA. We characterize site-specific FA binding by addition of (i) different FA molar ratios (from 1:1 to 4: ...
DOI:
10.1021/bi301458b

51. Covalent Allosteric Inactivation of Protein Tyrosine Phosphatase 1B (PTP1B) by an Inhibitor–Electrophile Conjugate

Author:
Punthasee Puminan; Laciak Adrian R.; Cummings Andrea H.; Ruddraraju Kasi Viswanatharaju; Lewis Sarah M.; Hillebrand Roman; Singh Harkewal; Tanner John J.; Gates Kent S.
Source:
Biochemistry 2017 v.56 no.14 pp. 2051-2060
ISSN:
1520-4995
Subject:
active sites; drugs; enzyme inactivation; mass spectrometry; protein-tyrosine-phosphatase
Abstract:
... Protein tyrosine phosphatase 1B (PTP1B) is a validated drug target, but it has proven difficult to develop medicinally useful, reversible inhibitors of this enzyme. Here we explored covalent strategies for the inactivation of PTP1B using a conjugate composed of an active site-directed 5-aryl-1,2,5-thiadiazolidin-3-one 1,1-dioxide inhibitor connected via a short linker to an electrophilic α-bromoac ...
DOI:
10.1021/acs.biochem.7b00151

52. Crowders Steal Dihydrofolate Reductase Ligands through Quinary Interactions

Author:
Michael R. Duff; Nidhi Desai; Michael A. Craig; Pratul K. Agarwal; Elizabeth E. Howell
Source:
Biochemistry 2019 v.58 no.9 pp. 1198-1213
ISSN:
1520-4995
Subject:
Escherichia coli; NADP (coenzyme); antibiotics; binding properties; carbon metabolism; computer simulation; dihydrofolate reductase; drug resistance; drugs; ligands; oxidation; proteins; solutes; tetrahydrofolic acid; trimethoprim
Abstract:
... Dihydrofolate reductase (DHFR) reduces dihydrofolate (DHF) to tetrahydrofolate using NADPH as a cofactor. Due to its role in one carbon metabolism, chromosomal DHFR is the target of the antibacterial drug, trimethoprim. Resistance to trimethoprim has resulted in a type II DHFR that is not structurally related to the chromosomal enzyme target. Because of its metabolic significance, understanding DH ...
DOI:
10.1021/acs.biochem.8b01110
PubMed:
30724552
PubMed Central:
PMC6589827

53. The Crystal Structure of Burkholderia cenocepacia DfsA Provides Insights into Substrate Recognition and Quorum Sensing Fatty Acid Biosynthesis

Author:
Spadaro Francesca; Scoffone Viola C.; Chiarelli Laurent R.; Fumagalli Marco; Buroni Silvia; Riccardi Giovanna; Forneris Federico
Source:
Biochemistry 2016 v.55 no.23 pp. 3241-3250
ISSN:
1520-4995
Subject:
Burkholderia cenocepacia; active sites; anti-infective agents; biofilm; biosynthesis; cell communication; communications technology; crystal structure; cystic fibrosis; dodecanoic acid; drugs; hydrophobicity; pathogens; patients; proteinases; quorum sensing; siderophores; virulence
Abstract:
... Burkholderia cenocepacia is a major concern among respiratory tract infections in cystic fibrosis patients. This pathogen is particularly difficult to treat because of its high level of resistance to the clinically relevant antimicrobial agents. In B. cenocepacia, the quorum sensing cell–cell communication system is involved in different processes that are important for bacterial virulence, such a ...
DOI:
10.1021/acs.biochem.6b00178

54. Crystal Structure of Schistosoma mansoni Arginase, a Potential Drug Target for the Treatment of Schistosomiasis

Author:
Hai Yang; Edwards Jennifer E.; Van Zandt Michael C.; Hoffmann Karl F.; Christianson David W.
Source:
Biochemistry 2014 v.53 no.28 pp. 4671-4684
ISSN:
1520-4995
Subject:
Schistosoma mansoni; X-ray diffraction; active sites; amino acid sequences; arginase; arginine; bioactive properties; biosynthesis; catalytic activity; crystal structure; drugs; humans; hydrolysis; immune evasion; immune response; manganese; nitric oxide; parasites; schistosomiasis; urea
Abstract:
... The X-ray crystal structure of arginase from Schistosoma mansoni (SmARG) and the structures of its complexes with several amino acid inhibitors have been determined at atomic resolution. SmARG is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea, and this enzyme is upregulated in all forms of the parasite that interact with the human host. ...
DOI:
10.1021/bi5004519
PubMed:
25007099
PubMed Central:
PMC4138072

55. The Crystal Structure of a Maxi/Mini-Ferritin Chimera Reveals Guiding Principles for the Assembly of Protein Cages

Author:
Thomas A. Cornell; Yogesh Srivastava; Ralf Jauch; Rongli Fan; Brendan P. Orner
Source:
Biochemistry 2017 v.56 no.30 pp. 3894-3899
ISSN:
1520-4995
Subject:
capsid; crystal structure; drugs; ferritin; homeostasis; iron; models; nanomaterials; protein quaternary structure; viruses
Abstract:
... Cage proteins assemble into nanoscale structures with large central cavities. They play roles, including those as virus capsids and chaperones, and have been applied to drug delivery and nanomaterials. Furthermore, protein cages have been used as model systems to understand and design protein quaternary structure. Ferritins are ubiquitous protein cages that manage iron homeostasis and oxidative da ...
DOI:
10.1021/acs.biochem.7b00312

56. Crystal Structure of an Arginase-like Protein from Trypanosoma brucei That Evolved without a Binuclear Manganese Cluster

Author:
Hai Yang; Kerkhoven Eduard J.; Barrett Michael P.; Christianson David W.
Source:
Biochemistry 2015 v.54 no.2 pp. 458-471
ISSN:
1520-4995
Subject:
Trypanosoma brucei; X-ray diffraction; active sites; amino acid sequences; antiparasitic agents; arginase; arginine; biochemical pathways; crystal structure; drugs; genes; manganese; metabolomics; metal ions; metalloproteins; ornithine decarboxylase; parasites; polyamines; sequence analysis; site-directed mutagenesis
Abstract:
... The X-ray crystal structure of an arginase-like protein from the parasitic protozoan Trypanosoma brucei, designated TbARG, is reported at 1.80 and 2.38 Å resolution in its reduced and oxidized forms, respectively. The oxidized form of TbARG is a disulfide-linked hexamer that retains the overall architecture of a dimer of trimers in the reduced form. Intriguingly, TbARG does not contain metal ions ...
DOI:
10.1021/bi501366a
PubMed:
25536859
PubMed Central:
PMC4303290

57. Crystal Structure of the Zorbamycin-Binding Protein ZbmA, the Primary Self-Resistance Element in Streptomyces flavoviridis ATCC21892

Author:
Rudolf Jeffrey D.; Bigelow Lance; Chang Changsoo; Cuff Marianne E.; Lohman Jeremy R.; Chang Chin-Yuan; Ma Ming; Yang Dong; Clancy Shonda; Babnigg Gyorgy; Joachimiak Andrzej; Phillips George N.; Shen Ben
Source:
Biochemistry 2015 v.54 no.45 pp. 6842-6851
ISSN:
1520-4995
Subject:
Streptoalloteichus hindustanus; Streptomyces flavoviridis; Streptomyces verticillus; antibiotics; binding proteins; copper; crystal structure; drugs; genes; oxygen
Abstract:
... The bleomycins (BLMs), tallysomycins (TLMs), phleomycin, and zorbamycin (ZBM) are members of the BLM family of glycopeptide-derived antitumor antibiotics. The BLM-producing Streptomyces verticillus ATCC15003 and the TLM-producing Streptoalloteichus hindustanus E465-94 ATCC31158 both possess at least two self-resistance elements, an N-acetyltransferase and a binding protein. The N-acetyltransferase ...
DOI:
10.1021/acs.biochem.5b01008
PubMed:
26512730
PubMed Central:
PMC4809751

58. Crystal Structures of Trypanosoma cruzi UDP-Galactopyranose Mutase Implicate Flexibility of the Histidine Loop in Enzyme Activation

Author:
Dhatwalia Richa; Singh Harkewal; Oppenheimer Michelle; Sobrado Pablo; Tanner John J.
Source:
Biochemistry 2012 v.51 no.24 pp. 4968-4979
ISSN:
1520-4995
Subject:
Aspergillus fumigatus; Chagas disease; Trypanosoma cruzi; catalytic activity; crystal structure; drugs; enzyme activation; enzyme activity; enzymes; glycolipids; glycoproteins; histidine; humans; mutants; mutation; parasites; pathogens; sequence alignment
Abstract:
... Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. Here we report crystal structures of the galactofuranose biosynthetic enzyme UDP-galactopyranose mutase (UGM) from T. cruzi, which are the first structures of this enzyme from a protozoan parasite. UGM is an attractive target for drug design because galactofuranose is absent in humans but is an essen ...
DOI:
10.1021/bi300498c
PubMed:
22646091
PubMed Central:
PMC3426654

59. Crystal structure of Tritrichomonas foetus inosine-5'-monophosphate dehydrogenase and the enzyme-product complex

Author:
Whitby, F.G.; Luecke, H.; Kuhn, P.; Somoza, J.R.; Huete-Perez, J.A.; Phillips, J.D.; Hill, C.P.; Fletterick, R.J.; Wang, C.C.
Source:
Biochemistry 1997 v.36 no.35 pp. 10666-10674
ISSN:
0006-2960
Subject:
Tritrichomonas foetus; active sites; arginine; biosynthesis; crystal structure; disulfide bonds; drugs; enzyme activity; guanosine monophosphate; inosine monophosphate; oxidation; parasites; parasitoses; phosphates; reducing agents
Abstract:
... Inosine-5'-monophosphate dehydrogenase (IMPDH) is an attractive drug target for the control of parasitic infections. The enzyme catalyzes the oxidation of inosine monophosphate (IMP)to xanthosine monophosphate (XMP), the committed step in de novo guanosine monophosphate (GMP) biosynthesis. We have determined the crystal structures of IMPDH from the protozoan parasite Tritrichomonas foetus in the a ...
DOI:
10.1021/bi9708850
PubMed:
9271497

60. Crystal structure of the hypoxanthine-guanine-xanthine phosphoribosyltransferase from the protozoan parasite Tritrichomonas foetus

Author:
Somoza, J.R.; Chin, M.S.; Focia, P.J.; Wang, C.C.; Fletterick, R.J.
Source:
Biochemistry 1996 v.35 no.22 pp. 7032-7040
ISSN:
0006-2960
Subject:
Tritrichomonas foetus; X-radiation; active sites; crystal structure; drugs; enzymes; guanosine monophosphate; humans; parasites; polypeptides
Abstract:
... The crystal structure of the hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRTase) from Tritrichomonas foetus has been determined and refined against X-ray data to 1.9 angstrom resolution. T. foetus HGXPRTase crystallizes as an asymmetric dimer, with GMP bound to only one of the two molecules that form the asymmetric unit. Each molecule of HGXPRTase is formed by two lobes joined by a ...
DOI:
10.1021/bi953072p
PubMed:
8679528

61. Crystallographic Structure of Truncated CCL21 and the Putative Sulfotyrosine-Binding Site

Author:
Smith Emmanuel W.; Lewandowski Eric M.; Moussouras Natasha A.; Kroeck Kyle G.; Volkman Brian F.; Veldkamp Christopher T.; Chen Yu
Source:
Biochemistry 2016 v.55 no.40 pp. 5746-5753
ISSN:
1520-4995
Subject:
CCR7 receptor; X-ray diffraction; chemokine CCL21; crystal structure; drugs; immune response; metastasis; neoplasms; nuclear magnetic resonance spectroscopy; tyrosine
Abstract:
... CCL21 chemokine binds the G protein-coupled receptor CCR7, aiding not only in immune response but also in cancer metastasis. Compared with other chemokines, CCL21 has a unique extended unstructured C-terminus that is truncated in some naturally occurring variants. We have determined the X-ray crystallographic structure of a truncated CCL21 (residues 1–79) lacking the extended C-terminus and identi ...
DOI:
10.1021/acs.biochem.6b00304
PubMed:
27617343
PubMed Central:
PMC5498006

62. A Cyclic Mimic of HIV Tat Differentiates Similar TAR RNAs on the Basis of Distinct Dynamic Behaviors

Author:
Lu Jia; Nguyen Larry; Zhao Liang; Xia Tianbing; Qi Xin
Source:
Biochemistry 2015 v.54 no.23 pp. 3687-3693
ISSN:
1520-4995
Subject:
Human immunodeficiency virus; RNA; binding sites; drugs; ligands; transcriptional activation
Abstract:
... Efforts toward the development of RNA-based drug leads have been challenging because of the complexity and dynamic nature of RNA structures as therapeutic targets. The transactivation response (TAR) RNA and cognate Tat protein of HIV have long been recognized as promising antiviral targets, and recent works have identified potentially potent inhibitors of the viral RNA–protein interaction. A new c ...
DOI:
10.1021/acs.biochem.5b00325

63. Cyclostreptin Derivatives Specifically Target Cellular Tubulin and Further Map the Paclitaxel Site

Author:
Calvo Enrique; Barasoain Isabel; Matesanz Ruth; Pera Benet; Camafeita Emilio; Pineda Oriol; Hamel Ernest; Vanderwal ChristopherD.; Andreu José Manuel; López Juan A.; Díaz José Fernando
Source:
Biochemistry 2012 v.51 no.1 pp. 329-341
ISSN:
1520-4995
Subject:
P-glycoproteins; binding sites; cytotoxicity; drugs; mechanism of action; microtubules; multiple drug resistance; neoplasm cells; paclitaxel; tubulin
Abstract:
... Cyclostreptin is the first microtubule-stabilizing agent whose mechanism of action was discovered to involve formation of a covalent bond with tubulin. Treatment of cells with cyclostreptin irreversibly stabilizes their microtubules because cyclostreptin forms a covalent bond to β-tubulin at either the T220 or the N228 residue, located at the microtubule pore or luminal taxoid binding site, respec ...
DOI:
10.1021/bi201380p
PubMed:
22148836
PubMed Central:
PMC3255483

64. Cyclotide Structure and Function: The Role of Membrane Binding and Permeation

Author:
Troeira Henriques Sónia; Craik David J.
Source:
Biochemistry 2017 v.56 no.5 pp. 669-682
ISSN:
1520-4995
Subject:
bioactive properties; cyclic peptides; drugs; phosphatidylethanolamines; physicochemical properties; trypsin inhibitors
Abstract:
... There is growing interest in the use of peptides as therapeutic drugs and, in particular, in the potential of cyclotides, a family of cyclic peptides with remarkable stability and amenability to sequence engineering, as scaffolds in drug design. As well as having an ultrastable structure, many natural cyclotides have intrinsic biological activities with potential pharmaceutical or agricultural app ...
DOI:
10.1021/acs.biochem.6b01212

65. Cysteine Disulfide Traps Reveal Distinct Conformational Ensembles in Dengue Virus NS2B-NS3 Protease

Author:
Maureen E. Hill; Muslum Yildiz; Jeanne A. Hardy
Source:
Biochemistry 2018 v.58 no.6 pp. 776-787
ISSN:
1520-4995
Subject:
Dengue virus; cysteine; dengue hemorrhagic fever; drugs; enzyme activity; polypeptides; proteinases; viral nonstructural proteins
Abstract:
... The dengue virus protease (NS2B-NS3pro) plays a critical role in the dengue viral life cycle, making it an attractive drug target for dengue-related pathologies, including dengue hemorrhagic fever. A number of studies indicate that NS2B-NS3pro undergoes a transition between two widely different conformational states: an “open” (inactive) conformation and a “closed” (active) conformation. For the p ...
DOI:
10.1021/acs.biochem.8b00978

66. Cysteine Scanning Mutagenesis of Transmembrane Domain 10 in Organic Anion Transporting Polypeptide 1B1

Author:
Ohnishi Shuichi; Hays Amanda; Hagenbuch Bruno
Source:
Biochemistry 2014 v.53 no.14 pp. 2261-2270
ISSN:
1520-4995
Subject:
binding sites; cysteine; drugs; hepatocytes; humans; mutagenesis; mutants; plasma membrane; polypeptides; sodium
Abstract:
... Organic anion transporting polypeptide (OATP) 1B1 is an important drug transporter expressed in human hepatocytes. Previous studies have indicated that transmembrane (TM) domain 2, 6, 8, 9, and in particular 10 might be part of the substrate binding site/translocation pathway. To explore which amino acids in TM10 are important for substrate transport, we mutated 34 amino acids individually to cyst ...
DOI:
10.1021/bi500176e
PubMed:
24673529
PubMed Central:
PMC4004239

67. Cytochrome b5 Activates the 17,20-Lyase Activity of Human Cytochrome P450 17A1 by Increasing the Coupling of NADPH Consumption to Androgen Production

Author:
Peng Hwei-Ming; Im Sang-Choul; Pearl Naw May; Turcu Adina F.; Rege Juilee; Waskell Lucy; Auchus Richard J.
Source:
Biochemistry 2016 v.55 no.31 pp. 4356-4365
ISSN:
1520-4995
Subject:
NADP (coenzyme); active sites; alanine; biosynthesis; cytochrome P-450; drugs; humans; mutation; oxidation; pregnenolone; progesterone; prostatic neoplasms; threonine
Abstract:
... Human cytochrome P450 17A1 is required for all androgen biosynthesis and is the target of abiraterone, a drug used widely to treat advanced prostate cancer. P450 17A1 catalyzes both 17-hydroxylation and subsequent 17,20-lyase reactions with pregnenolone, progesterone, and allopregnanolone. The presence of cytochrome b₅ (b5) markedly stimulates the 17,20-lyase reaction, with little effect on 17-hyd ...
DOI:
10.1021/acs.biochem.6b00532
PubMed:
27426448
PubMed Central:
PMC5287367

68. DNA Consensus Sequence Motif for Binding Response Regulator PhoP, a Virulence Regulator of Mycobacterium tuberculosis

Author:
He Xiaoyuan; Wang Shuishu
Source:
Biochemistry 2014 v.53 no.51 pp. 8008-8020
ISSN:
1520-4995
Subject:
DNA; DNA fragmentation; HIV infections; Human immunodeficiency virus; Mycobacterium tuberculosis; calorimetry; consensus sequence; drug resistance; drugs; gel electrophoresis; genes; human health; pathogens; phosphorylation; promoter regions; systematic evolution of ligands by exponential enrichment; titration; transcription (genetics); tuberculosis; virulence
Abstract:
... Tuberculosis has reemerged as a serious threat to human health because of the increasing prevalence of drug-resistant strains and synergetic infection with HIV, prompting an urgent need for new and more efficient treatments. The PhoP–PhoR two-component system of Mycobacterium tuberculosis plays an important role in the virulence of the pathogen and thus represents a potential drug target. To study ...
DOI:
10.1021/bi501019u
PubMed:
25434965
PubMed Central:
PMC4283936

69. DNA Cytosine Methylation: Structural and Thermodynamic Characterization of the Epigenetic Marking Mechanism

Author:
Yang Jin; Lior-Hoffmann Lee; Wang Shenglong; Zhang Yingkai; Broyde Suse
Source:
Biochemistry 2013 v.52 no.16 pp. 2828-2838
ISSN:
1520-4995
Subject:
DNA; DNA methylation; S-adenosylmethionine; active sites; cytosine; drugs; energy; epigenetics; genome; human diseases; mammals; methyltransferases; molecular dynamics; neoplasms; prokaryotic cells; thermodynamics
Abstract:
... DNA cytosine methyltransferases regulate the expression of the genome through the precise epigenetic marking of certain cytosines with a methyl group, and aberrant methylation is a hallmark of human diseases including cancer. Targeting these enzymes for drug design is currently a high priority. We have utilized ab initio quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simul ...
DOI:
10.1021/bi400163k
PubMed:
23528166
PubMed Central:
PMC3687104

70. Design, Synthesis, and Experimental Validation of Peptide Ligands Targeting Mycobacterium tuberculosis σ Factors

Author:
Vishwanath Sneha; Banerjee Sunaina; Jamithireddy Anil K.; Srinivasan Narayanaswamy; Gopal Balasubramanian; Chatterjee Jayanta
Source:
Biochemistry 2017 v.56 no.16 pp. 2209-2218
ISSN:
1520-4995
Subject:
DNA-directed RNA polymerase; Mycobacterium tuberculosis; bacteria; drugs; gene expression; host-pathogen relationships; interferometry; ligands; peptide libraries; prokaryotic cells; sigma factors
Abstract:
... Transcription in prokaryotes is a multistep process and is primarily regulated at the initiation stage. σ factors are involved in promoter recognition and thus govern prokaryotic gene expression. Mycobacterium tuberculosis (Mtb) σ factors have been previously suggested as important drug targets through large-scale genome analyses. Here we demonstrate the feasibility of specific targeting of Mtb σ ...
DOI:
10.1021/acs.biochem.6b01267

71. Design, Synthesis, and Investigation of Novel Nitric Oxide (NO)-Releasing Prodrugs as Drug Candidates for the Treatment of Ischemic Disorders: Insights into NO-Releasing Prodrug Biotransformation and Hemoglobin–NO Biochemistry

Author:
Xu Guoyan G.; Deshpande Tanvi M.; Ghatge Mohini S.; Mehta Akul Y.; Omar Abdel Sattar M.; Ahmed Mostafa H.; Venitz Jurgen; Abdulmalik Osheiza; Zhang Yan; Safo Martin K.
Source:
Biochemistry 2015 v.54 no.49 pp. 7178-7192
ISSN:
1520-4995
Subject:
biotransformation; blood flow; blood serum; cardiovascular diseases; cysteine; drugs; hemoglobin; humans; hydrolysis; in vitro studies; ischemia; liquid chromatography; mass spectrometry; mechanism of action; nitrates; nitric oxide; oxygen
Abstract:
... We have developed novel nitric oxide (NO)-releasing prodrugs of efaproxiral (RSR13) for their potential therapeutic applications in a variety of diseases with underlying ischemia. RSR13 is an allosteric effector of hemoglobin (Hb) that decreases the protein’s affinity for oxygen, thereby increasing tissue oxygenation. NO, because of its vasodilatory property, in the form of ester prodrugs has been ...
DOI:
10.1021/acs.biochem.5b01074
PubMed:
26582149
PubMed Central:
PMC5453643

72. Desleucyl-Oritavancin with a Damaged d-Ala-d-Ala Binding Site Inhibits the Transpeptidation Step of Cell-Wall Biosynthesis in Whole Cells of Staphylococcus aureus

Author:
Kim Sung Joon; Singh Manmilan; Sharif Shasad; Schaefer Jacob
Source:
Biochemistry 2017 v.56 no.10 pp. 1529-1535
ISSN:
1520-4995
Subject:
Staphylococcus aureus; binding sites; biosynthesis; biphenyl; crosslinking; drugs; glycopeptides; hydrophobicity; mechanism of action; nuclear magnetic resonance spectroscopy; peptidoglycans
Abstract:
... We have used solid-state nuclear magnetic resonance to characterize the exact nature of the dual mode of action of oritavancin in preventing cell-wall assembly in Staphylococcus aureus. Measurements performed on whole cells labeled selectively in vivo have established that des-N-methylleucyl-N-4-(4-fluorophenyl)benzyl-chloroeremomycin, an Edman degradation product of [¹⁹F]oritavancin, which has a ...
DOI:
10.1021/acs.biochem.6b01125
PubMed:
28221772
PubMed Central:
PMC5508972

73. Detergent Optimized Membrane Protein Reconstitution in Liposomes for Solid State NMR

Author:
Murray Dylan T.; Griffin James; Cross Timothy A.
Source:
Biochemistry 2014 v.53 no.15 pp. 2454-2463
ISSN:
1520-4995
Subject:
Mycobacterium tuberculosis; binding properties; detergents; dialysis; drugs; lipid bilayers; lipids; membrane proteins; nuclear magnetic resonance spectroscopy; solubilization
Abstract:
... For small helical membrane proteins, their structures are highly sensitive to their environment, and solid state NMR is a structural technique that can characterize these membrane proteins in native-like lipid bilayers and proteoliposomes. To date, a systematic method by which to evaluate the effect of the solubilizing detergent on proteoliposome preparations for solid state NMR of membrane protei ...
DOI:
10.1021/bi500144h
PubMed:
24665863
PubMed Central:
PMC4004220

74. Detergent-Type Membrane Fragmentation by MSI-78, MSI-367, MSI-594, and MSI-843 Antimicrobial Peptides and Inhibition by Cholesterol: A Solid-State Nuclear Magnetic Resonance Study

Author:
Lee Dong-Kuk; Bhunia Anirban; Kotler Samuel A.; Ramamoorthy Ayyalusamy
Source:
Biochemistry 2015 v.54 no.10 pp. 1897-1907
ISSN:
1520-4995
Subject:
adenosine monophosphate; amino acid sequences; antibiotics; antimicrobial cationic peptides; bacteria; cholesterol; circular dichroism spectroscopy; drugs; eukaryotic cells; lipid bilayers; mechanism of action; micelles; multiple drug resistance; nuclear magnetic resonance spectroscopy; zwitterions
Abstract:
... Multidrug resistance against the existing antibiotics is becoming a global threat, and any potential drug that can be designed using cationic antimicrobial peptides (AMP) could be an alternate solution to alleviate this existing problem. The mechanism of action of killing bacteria by an AMP differs drastically in comparison to that of small molecule antibiotics. The main target of AMPs is to inter ...
DOI:
10.1021/bi501418m

75. Determination of a Structural Ensemble Representing the Dynamics of a G-Quadruplex DNA

Author:
Guillem Portella; Modesto Orozco; Michele Vendruscolo
Source:
Biochemistry 2019 v.59 no.4 pp. 379-388
ISSN:
1520-4995
Subject:
cations; couplings; drugs; dynamics; environmental factors; guanine; humans; molecular dynamics; nuclear magnetic resonance spectroscopy; nucleotides; single-stranded DNA; thermodynamics
Abstract:
... It is increasingly recognized that the structures and dynamics of G-quadruplex DNA molecules are dictated by their sequences and greatly affected by environmental factors. The core guanine tetrads (G-tetrads) coordinate cations and display a strong conformational rigidity compared with that of the connecting loops. Although long loops linking the G-tetrads are typically disfavored, when present, t ...
DOI:
10.1021/acs.biochem.9b00493

76. Development of a Cell-Based Ligand-Screening System for Identifying Hsp90 Inhibitors

Author:
Tsuyoshi Ueda; Tomonori Tamura; Itaru Hamachi
Source:
Biochemistry 2019 v.59 no.2 pp. 179-182
ISSN:
1520-4995
Subject:
ABC transporters; assays; cells; drugs; heat-shock protein 90; inflammation; libraries; ligands; nervous system diseases; screening; signal transduction; therapeutics
Abstract:
... Because of its critical roles in regulating cellular signal transduction, the molecular chaperone heat-shock protein 90 (Hsp90) has become a novel therapeutic target for various diseases, including cancer, inflammation, and neurological diseases. However, the lack of methods that allow us to directly evaluate the binding of small molecule ligands to intracellular Hsp90 makes the inhibitor developm ...
DOI:
10.1021/acs.biochem.9b00781

77. Different Roles of TM5, TM6, and ECL3 in the Oligomerization and Function of Human ABCG2

Author:
Mo Wei; Qi Jing; Zhang Jian-Ting
Source:
Biochemistry 2012 v.51 no.17 pp. 3634-3641
ISSN:
1520-4995
Subject:
ABC transporters; cytotoxicity; drug therapy; drugs; humans; multiple drug resistance; neoplasms; oligomerization; site-directed mutagenesis; stem cells
Abstract:
... ABCG2 is a member of the ATP-binding cassette transporter superfamily, and its overexpression causes multidrug resistance (MDR) in cancer chemotherapy. ABCG2 may also protect cancer stem cells by extruding cytotoxic materials. ABCG2 has previously been shown to exist as a high-order homo-oligomer consisting of possibly 8–12 subunits, and the oligomerization domain was mapped to the C-terminal doma ...
DOI:
10.1021/bi300301a

78. Differential Large-Amplitude Breathing Motions in the Interface of FKBP12–Drug Complexes†

Author:
Yang Chun-Jiun; Takeda Mitsuhiro; Terauchi Tsutomu; Jee JunGoo; Kainosho Masatsune
Source:
Biochemistry 2015 v.54 no.47 pp. 6983-6995
ISSN:
1520-4995
Subject:
X-ray diffraction; aromatic compounds; biochemistry; breathing; dissociation; drugs; hydrogen bonding; hydrophobicity; immunosuppression; ligands; models; nuclear magnetic resonance spectroscopy; oxygen
Abstract:
... The tight complexes FKBP12 forms with immunosuppressive drugs, such as FK506 and rapamycin, are frequently used as models for developing approaches to structure-based drug design. Although the interfaces between FKBP12 and these ligands are well-defined structurally and are almost identical in the X-ray crystallographic structures of various complexes, our nuclear magnetic resonance studies have r ...
DOI:
10.1021/acs.biochem.5b00820

79. Dihydroartemisinin–Ferriprotoporphyrin IX Adduct Abundance in Plasmodium falciparum Malarial Parasites and the Relationship to Emerging Artemisinin Resistance

Author:
Laura E. Heller; Eibhlin Goggins; Paul D. Roepe
Source:
Biochemistry 2018 v.57 no.51 pp. 6935-6945
ISSN:
1520-4995
Subject:
Plasmodium falciparum; artemisinin; drugs; heme; models; mutants; parasites; pharmacology; phenotype; prediction
Abstract:
... Previously (Heller, L. E., and Roepe, P. D. Quantification of Free Ferriprotoporphyrin IX Heme and Hemozoin for Artemisinin Sensitive versus Delayed Clearance Phenotype Plasmodium falciparum Malarial Parasites. Biochemistry, DOI: 10.1021/acs.biochem.8b00959, preceding paper in this issue), we quantified free ferriprotoporphyrin IX (FPIX) heme abundance for control versus delayed clearance phenotyp ...
DOI:
10.1021/acs.biochem.8b00960

80. Direct Antibody Isolation on Cells Using Affinity-Tag-Guided Proximity Selection

Author:
You-Chiun Chang; Chia-Yi Kao; Hao-Cheng Tang; Meng-Sen Huang; Kurt Yun Mou
Source:
Biochemistry 2020 v.59 no.44 pp. 4285-4293
ISSN:
1520-4995
Subject:
antibodies; antigens; bacteriophages; drugs; flow cytometry; fluorescent antibody technique; humans; immunization; solutes
Abstract:
... Traditional antibody generation, using either phage display or animal immunization, relies on purified antigens. Many membrane proteins, such as G protein-coupled receptors, solute carriers, or ion channels, are important drug targets but very challenging for the formation of antibodies due to the difficulty of protein purification. Whole-cell panning is an alternative approach for generating anti ...
DOI:
10.1021/acs.biochem.0c00730

81. Direct Capture of Functional Proteins from Mammalian Plasma Membranes into Nanodiscs

Author:
Roy Jahnabi; Pondenis Holly; Fan Timothy M.; Das Aditi
Source:
Biochemistry 2015 v.54 no.41 pp. 6299-6302
ISSN:
1520-4995
Subject:
cell free system; drugs; encapsulation; lipid composition; mammals; membrane proteins; peptide mapping; plasma membrane; proteome; receptor protein-tyrosine kinase
Abstract:
... Mammalian plasma membrane proteins make up the largest class of drug targets yet are difficult to study in a cell free system because of their intransigent nature. Herein, we perform direct encapsulation of plasma membrane proteins derived from mammalian cells into a functional nanodisc library. Peptide fingerprinting was used to analyze the proteome of the incorporated proteins in nanodiscs and t ...
DOI:
10.1021/acs.biochem.5b00954

82. Discovery and Characterization of a Novel Allosteric Small-Molecule Inhibitor of NADP⁺-Dependent Malic Enzyme 1

Author:
Tomohiro Yoshida; Tetsuhiro Kawabe; Lewis C. Cantley; Costas A. Lyssiotis
Source:
Biochemistry 2022 v.61 no.15 pp. 1548-1553
ISSN:
1520-4995
Subject:
active sites; crystal structure; cytoplasm; drugs; malates; malic enzyme; pyruvic acid
Abstract:
... NADP⁺-dependent malic enzyme 1 (ME1) decarboxylates malate to form pyruvate and NADPH in the cytoplasm, where it mediates diverse biological functions related to the generation of lipids and other cellular building blocks. As such, ME1 has been implicated in the progression of cancers and has received attention as a promising drug target. Here we report the identification of a novel small-molecule ...
DOI:
10.1021/acs.biochem.2c00123

83. Discovery of Inactive Conformation-Selective Kinase Inhibitors by Utilizing Cascade Assays

Author:
Wang Weixue; Krosky Daniel; Ahn Kay
Source:
Biochemistry 2017 v.56 no.34 pp. 4449-4456
ISSN:
1520-4995
Subject:
biochemistry; drugs; guidelines; humans; mathematical models
Abstract:
... Achieving selectivity across the human kinome is a major hurdle in kinase inhibitor drug discovery. Targeting inactive (vs active) kinase conformations offers advantages in achieving selectivity because of their more diversified structures. Discovery of inactive conformation-selective inhibitors, however, has been hampered partly by the lack of general assay methods. Herein, we show that such inhi ...
DOI:
10.1021/acs.biochem.7b00521

84. Discovery of an Allosteric, Inactive Conformation-Selective Inhibitor of Full-Length HPK1 Utilizing a Kinase Cascade Assay

Author:
Weixue Wang; Laurence Mevellec; Annie Liu; Geoff Struble; Robyn Miller; Samantha J. Allen; Kelly Federowicz; Berthold Wroblowski; Jorge Vialard; Kay Ahn; Daniel Krosky
Source:
Biochemistry 2021 v.60 no.41 pp. 3114-3124
ISSN:
1520-4995
Subject:
T-lymphocytes; adenosine triphosphate; drugs; humans; immunotherapy; protein phosphorylation; serine; threonine
Abstract:
... Achieving selectivity across the human kinome is a major hurdle in kinase inhibitor drug discovery. Assays using active, phosphorylated protein kinases bias hits toward poorly selective inhibitors that bind within the highly conserved adenosine triphosphate (ATP) pocket. Targeting inactive (vs active) kinase conformations offers advantages in achieving selectivity because of their more diversified ...
DOI:
10.1021/acs.biochem.1c00486

85. Discovery of an Irreversible and Cell-Active BCL6 Inhibitor Selectively Targeting Cys53 Located at the Protein–Protein Interaction Interface

Author:
Tomoya Sameshima; Takeshi Yamamoto; Osamu Sano; Satoshi Sogabe; Shigeru Igaki; Kotaro Sakamoto; Koh Ida; Mika Gotou; Yasuhiro Imaeda; Junichi Sakamoto; Ikuo Miyahisa
Source:
Biochemistry 2018 v.57 no.8 pp. 1369-1379
ISSN:
1520-4995
Subject:
B-cell lymphoma; cell growth; drugs; growth retardation; oncogenes; protein-protein interactions; repressor proteins; screening
Abstract:
... B-cell lymphoma 6 (BCL6) is the most frequently involved oncogene in diffuse large B-cell lymphomas (DLBCLs). BCL6 shows potent transcriptional repressor activity through interactions with its corepressors, such as BCL6 corepressor (BCOR). The inhibition of the protein–protein interaction (PPI) between BCL6 and its corepressors suppresses the growth of BCL6-dependent DLBCLs, thus making BCL6 an at ...
DOI:
10.1021/acs.biochem.7b00732

86. Discrimination of Ligands with Different Flexibilities Resulting from the Plasticity of the Binding Site in Tubulin

Author:
Chakraborti Soumyananda; Chakravarty Devlina; Gupta Suvroma; Chatterji Biswa Prasun; Dhar Gopa; Poddar Asim; Panda Dulal; Chakrabarti Pinak; Ghosh Dastidar Shubhra; Bhattacharyya Bhabatarak
Source:
Biochemistry 2012 v.51 no.36 pp. 7138-7148
ISSN:
1520-4995
Subject:
Vinca; binding sites; cell division; colchicine; drugs; enthalpy; entropy; flight; ligands; molecular dynamics; paclitaxel; rocks; tubulin; van der Waals forces
Abstract:
... Tubulin, an α,β heterodimer, has four distinct ligand binding sites (for paclitaxel, peloruside/laulimalide, vinca, and colchicine). The site where colchicine binds is a promising drug target for arresting cell division and has been observed to accommodate compounds that are structurally diverse but possess comparable affinity. This investigation, using two such structurally different ligands as p ...
DOI:
10.1021/bi300474q

87. Discrimination of Potent Inhibitors of Toxoplasma gondii Enoyl-Acyl Carrier Protein Reductase by a Thermal Shift Assay

Author:
Afanador Gustavo A.; Muench Stephen P.; McPhillie Martin; Fomovska Alina; Schön Arne; Zhou Ying; Cheng Gang; Stec Jozef; Freundlich Joel S.; Shieh Hong-Ming; Anderson John W.; Jacobus David P.; Fidock David A.; Kozikowski Alan P.; Fishwick Colin W.; Rice David W.; Freire Ernesto; McLeod Rima; Prigge Sean T.
Source:
Biochemistry 2013 v.52 no.51 pp. 9155-9166
ISSN:
1520-4995
Subject:
NAD (coenzyme); Toxoplasma gondii; biocides; dissociation; drugs; enzyme inhibition; fatty acids; humans; mechanism of action; medicine; parasites; pathogens; prediction
Abstract:
... Many microbial pathogens rely on a type II fatty acid synthesis (FASII) pathway that is distinct from the type I pathway found in humans. Enoyl-acyl carrier protein reductase (ENR) is an essential FASII pathway enzyme and the target of a number of antimicrobial drug discovery efforts. The biocide triclosan is established as a potent inhibitor of ENR and has been the starting point for medicinal ch ...
DOI:
10.1021/bi400945y
PubMed:
24295325
PubMed Central:
PMC3953223

88. Dissect Conformational Distribution and Drug-Induced Population Shift of Prokaryotic rRNA A-Site

Author:
Lu Jia; Zhao Liang; Xia Amy; Xia Tianbing; Qi Xin
Source:
Biochemistry 2013 v.52 no.10 pp. 1651-1653
ISSN:
1520-4995
Subject:
anti-infective agents; drugs; nucleic acid conformation; prokaryotic cells; ribosomal RNA; spectroscopy
Abstract:
... The dynamic behavior of the rRNA A-site plays an important functional role. We have employed femtosecond time-resolved spectroscopy to investigate the nature of the conformational dynamics. In the drug-free state, the A-site samples multiple distinct conformations. Drug binding shifts the population distribution in a drug-specific manner. Motions of bases on nanosecond and picosecond time scales a ...
DOI:
10.1021/bi400053s

89. Distinct Conformational Transition Patterns of Noncoding 7SK snRNA and HIV TAR RNAs upon Tat Binding

Author:
Lu Jia; Wong Vivian; Zhang Yi; Tran Trung; Zhao Liang; Xia Amy; Xia Tianbing; Qi Xin
Source:
Biochemistry 2014 v.53 no.4 pp. 675-681
ISSN:
1520-4995
Subject:
Human immunodeficiency virus 1; Human immunodeficiency virus 2; drugs; fluorescence emission spectroscopy; small nuclear RNA
Abstract:
... Noncoding 7SK snRNA is believed to play an important role in the recruitment of P-TEFb by viral protein Tat to stimulate HIV processive transcription. Because HIV-2 TAR RNA and 7SK both evolved to feature a dinucleotide bulge region, compared to the trinucleotide bulge for HIV-1 TAR, ultrafast time-resolved fluorescence spectroscopy has been used to probe the conformational landscape of HIV-2 TAR ...
DOI:
10.1021/bi401131z
PubMed:
24422492
PubMed Central:
PMC3985858

90. Distinct Roles of Apolipoproteins A1 and E in the Modulation of High-Density Lipoprotein Composition and Function

Author:
Filou Serafoula; Lhomme Marie; Karavia Eleni A.; Kalogeropoulou Christina; Theodoropoulos Vassilis; Zvintzou Evangelia; Sakellaropoulos George C.; Petropoulou Peristera-Ioanna; Constantinou Caterina; Kontush Anatol; Kypreos Kyriakos E.
Source:
Biochemistry 2016 v.55 no.27 pp. 3752-3762
ISSN:
1520-4995
Subject:
Adenoviridae; Western blotting; adenosine triphosphate; anti-inflammatory activity; antioxidant activity; apolipoprotein A-I; apolipoprotein E; biogenesis; drugs; high density lipoprotein cholesterol; human health; lipid composition; mice; tumor necrosis factor-alpha
Abstract:
... In addition to high-density lipoprotein cholesterol (HDL-C) levels, HDL quality also appears to be very important for atheroprotection. Analysis of various clinical paradigms suggests that the lipid and apolipoprotein composition of HDL defines its size, shape, and functions and may determine its beneficial effects on human health. Previously, we reported that like apolipoprotein A-I (Apoa1), apol ...
DOI:
10.1021/acs.biochem.6b00389

91. Distinguishing the Interactions in the Fructose 1,6-Bisphosphate Binding Site of Human Liver Pyruvate Kinase That Contribute to Allostery

Author:
Ishwar Arjun; Tang Qingling; Fenton Aron W.
Source:
Biochemistry 2015 v.54 no.7 pp. 1516-1524
ISSN:
1520-4995
Subject:
binding sites; chemical elements; drugs; fructose; glucose; glycemic effect; humans; hydrogen bonding; liver; mutagenesis; mutants; phosphates; proteins; pyruvate kinase; ribulose 1,5-diphosphate
Abstract:
... In the study of allosteric proteins, understanding which effector–protein interactions contribute to allosteric activation is important both for designing allosteric drugs and for understanding allosteric mechanisms. The antihyperglycemic target, human liver pyruvate kinase (hL-PYK), binds its allosteric activator, fructose 1,6-bisphosphate (Fru-1,6-BP), such that the 1′-phosphate interacts with s ...
DOI:
10.1021/bi501426w
PubMed:
25629396
PubMed Central:
PMC5286843

92. Disulfide Bridging Strategies in Viral and Nonviral Platforms for Nucleic Acid Delivery

Author:
Kingshuk Dutta; Ritam Das; Jewel Medeiros; S. Thayumanavan
Source:
Biochemistry 2021 v.60 no.13 pp. 966-990
ISSN:
1520-4995
Subject:
dendrimers; disulfides; drugs; encapsulation; hydrogels; nucleic acids; peptides
Abstract:
... Self-assembled nanostructures that are sensitive to environmental stimuli are promising nanomaterials for drug delivery. In this class, disulfide-containing redox-sensitive strategies have gained enormous attention because of their wide applicability and simplicity of nanoparticle design. In the context of nucleic acid delivery, numerous disulfide-based materials have been designed by relying on c ...
DOI:
10.1021/acs.biochem.0c00860

93. Domain Structure and Denaturation of a Dimeric Mip-like Peptidyl-Prolyl cis–trans Isomerase from Escherichia coli

Author:
Jana Biswanath; Bandhu Amitava; Mondal Rajkrishna; Biswas Anindya; Sau Keya; Sau Subrata
Source:
Biochemistry 2012 v.51 no.6 pp. 1223-1237
ISSN:
1520-4995
Subject:
Escherichia coli; Legionella; denaturation; drugs; guanidines; immunosuppression; peptidylprolyl isomerase; proteins; proteolysis; urea; virulence
Abstract:
... FKBP22, a protein expressed by Escherichia coli, possesses PPIase (peptidyl-prolyl cis-trans isomerase) activity, binds FK506 (an immunosuppressive drug), and shares homology with Legionella Mip (a virulence factor) and its related proteins. To understand the domain structure and the folding–unfolding mechanism of Mip-like proteins, we investigated a recombinant E. coli FKBP22 (His-FKBP22) as a mo ...
DOI:
10.1021/bi2015037

94. Drug Interactions with Bacillus anthracis Topoisomerase IV: Biochemical Basis for Quinolone Action and Resistance

Author:
Aldred KatieJ.; McPherson Sylvia A.; Wang Pengfei; Kerns Robert J.; Graves David E.; Turnbough Charles L.; Osheroff Neil
Source:
Biochemistry 2012 v.51 no.1 pp. 370-381
ISSN:
1520-4995
Subject:
Bacillus anthracis; DNA; DNA damage; DNA topoisomerase; catalytic activity; ciprofloxacin; drug interactions; drugs; magnesium; mutants; mutation; serine
Abstract:
... Bacillus anthracis, the causative agent of anthrax, is considered a serious threat as a bioweapon. The drugs most commonly used to treat anthrax are quinolones, which act by increasing the levels of DNA cleavage mediated by topoisomerase IV and gyrase. Quinolone resistance most often is associated with specific serine mutations in these enzymes. Therefore, to determine the basis for quinolone acti ...
DOI:
10.1021/bi2013905
PubMed:
22126453
PubMed Central:
PMC3261753

95. Drug Modulation of Water–Heme Interactions in Low-Spin P450 Complexes of CYP2C9d and CYP125A1

Author:
Conner Kip P.; Cruce Alex A.; Krzyaniak Matthew D.; Schimpf Alina M.; Frank Daniel J.; Ortiz de Montellano Paul; Atkins William M.; Bowman Michael K.
Source:
Biochemistry 2015 v.54 no.5 pp. 1198-1207
ISSN:
1520-4995
Subject:
Mycobacterium tuberculosis; X-ray diffraction; absorbance; active sites; azoles; binding capacity; circular dichroism spectroscopy; cytochrome P-450; drugs; electron paramagnetic resonance spectroscopy; heme iron; nitrogen; pyridines; stable isotopes
Abstract:
... Azoles and pyridines are commonly incorporated into small molecule inhibitor scaffolds that target cytochromes P450 (CYPs) as a strategy to increase drug binding affinity, impart isoform-dependent selectivity, and improve metabolic stability. Optical absorbance spectra of the CYP–inhibitor complex are widely used to infer whether these inhibitors are ligated directly to the heme iron as catalytica ...
DOI:
10.1021/bi501402k
PubMed:
25591012
PubMed Central:
PMC4437715

96. Drug Rescue Distinguishes between Different Structural Models of Human P-Glycoprotein

Author:
Loo Tip W.; Clarke David M.
Source:
Biochemistry 2013 v.52 no.41 pp. 7167-7169
ISSN:
1520-4995
Subject:
Caenorhabditis elegans; P-glycoproteins; arginine; crystal structure; drugs; humans; lipids; mice; models; mutants
Abstract:
... There is no high-resolution crystal structure of the human P-glycoprotein (P-gp) drug pump. Homology models of human P-gp based on the crystal structures of mouse or Caenorhabditis elegans P-gps show large differences in the orientation of transmembrane segment 5 (TM5). TM5 is one of the most important transmembrane segments involved in drug–substrate interactions. Drug rescue of P-gp processing m ...
DOI:
10.1021/bi401269m
PubMed:
24083983
PubMed Central:
PMC3798097

97. Drugging the Undruggable: How Isoquinolines and PKA Initiated the Era of Designed Protein Kinase Inhibitor Therapeutics

Author:
Robin Lorenz; Jian Wu; Friedrich W. Herberg; Susan S. Taylor; Richard A. Engh
Source:
Biochemistry 2021 v.60 no.46 pp. 3470-3484
ISSN:
1520-4995
Subject:
adenosine; artificial intelligence; cAMP-dependent protein kinase; drugs; glycine (amino acid); isoquinolines; nuclear magnetic resonance spectroscopy; prototypes; therapeutics
Abstract:
... In 1984, Japanese researchers led by the biochemist Hiroyoshi Hidaka described the first synthetic protein kinase inhibitors based on an isoquinoline sulfonamide structure (Hidaka et al. Biochemistry, 1984 Oct 9; 23(21): 5036–41. doi: 10.1021/bi00316a032). These led to the first protein kinase inhibitor approved for medical use (fasudil), an inhibitor of the AGC subfamily Rho kinase. With potencie ...
DOI:
10.1021/acs.biochem.1c00359

98. Drugs Modulate Interactions between the First Nucleotide-Binding Domain and the Fourth Cytoplasmic Loop of Human P-Glycoprotein

Author:
Loo Tip W.; Clarke David M.
Source:
Biochemistry 2016 v.55 no.20 pp. 2817-2820
ISSN:
1520-4995
Subject:
P-glycoproteins; adenosinetriphosphatase; crosslinking; drugs; humans; lipids
Abstract:
... Drug substrates stimulate ATPase activity of the P-glycoprotein (P-gp) ATP-binding cassette drug pump by an unknown mechanism. Cross-linking analysis was performed to test if drug substrates stimulate P-gp ATPase activity by altering cross-talk at the first transmission interface linking the drug-binding [intracellular loop 4 (S909C)] and first nucleotide-binding domains [NBD1 (V472C or L443C)]. I ...
DOI:
10.1021/acs.biochem.6b00233

99. Drug–Drug Interactions between Atorvastatin and Dronedarone Mediated by Monomeric CYP3A4

Author:
Ilia G. Denisov; Javier L. Baylon; Yelena V. Grinkova; Emad Tajkhorshid; Stephen G. Sligar
Source:
Biochemistry 2018 v.57 no.5 pp. 805-816
ISSN:
1520-4995
Subject:
active sites; drug interactions; drugs; metabolism; molecular dynamics; simulation models
Abstract:
... Heterotropic interactions between atorvastatin (ARVS) and dronedarone (DND) have been deciphered using global analysis of the results of binding and turnover experiments for pure drugs and their mixtures. The in vivo presence of atorvastatin lactone (ARVL) was explicitly taken into account by using pure ARVL in analogous experiments. Both ARVL and ARVS inhibit DND binding and metabolism, while a s ...
DOI:
10.1021/acs.biochem.7b01012
PubMed:
29200287
PubMed Central:
PMC5800941

100. Drug–Membrane Interactions: Effects of Virus-Specific RNA-Dependent RNA Polymerase Inhibitors Remdesivir and Favipiravir on the Structure of Lipid Bilayers

Author:
Markus Fischer; Peter Müller; Holger A. Scheidt; Meike Luck
Source:
Biochemistry 2022 v.61 no.13 pp. 1392-1403
ISSN:
1520-4995
Subject:
COVID-19 infection; RNA-directed RNA polymerase; Severe acute respiratory syndrome coronavirus 2; drugs; erythrocytes; hemolysis; influenza; lipid bilayers; models; pandemic; permeability; phospholipids; plasma membrane; therapeutics
Abstract:
... The two RNA-dependent RNA polymerase inhibitors remdesivir and favipiravir were originally developed and approved as broad-spectrum antiviral drugs for the treatment of harmful viral infections such as Ebola and influenza. With the outbreak of the global SARS-CoV-2 pandemic, the two drugs were repurposed for the treatment of COVID-19 patients. Clinical studies suggested that the efficacy of the dr ...
DOI:
10.1021/acs.biochem.2c00042