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1. Advances in Molecular Modeling of Human Cytochrome P450 Polymorphism

Author:
Martiny, Virginie Y.; Miteva, Maria A.
Source:
Journal of Molecular Biology 2013 v.425 pp. 3978-3992
ISSN:
0022-2836
Subject:
adverse effects; carcinogenicity; cytochrome P-450; drugs; enzymes; humans; metabolism; metabolites; models; oxidation
Abstract:
... Cytochrome P450 (CYP) is a supergene family of metabolizing enzymes involved in the phase I metabolism of drugs and endogenous compounds. CYP oxidation often leads to inactive drug metabolites or to highly toxic or carcinogenic metabolites involved in adverse drug reactions (ADR). During the last decade, the impact of CYP polymorphism in various drug responses and ADR has been demonstrated. Of the ...
DOI:
10.1016/j.jmb.2013.07.010
PubMed:
23856621

2. An Inhibitory Antibody Blocks the First Step in the Dithiol/Disulfide Relay Mechanism of the Enzyme QSOX1

Author:
Grossman, Iris; Alon, Assaf; Ilani, Tal; Fass, Deborah
Source:
Journal of Molecular Biology 2013 v.425 pp. 4366-4378
ISSN:
0022-2836
Subject:
adenocarcinoma; catalysts; cell adhesion; cell movement; cell viability; disulfide bonds; electron transfer; extracellular matrix; fibroblasts; humans; laminin; metastasis; models; monoclonal antibodies; mutagenesis; neoplasm cells; secretion; sulfides
Abstract:
... Quiescin sulfhydryl oxidase 1 (QSOX1) is a catalyst of disulfide bond formation that undergoes regulated secretion from fibroblasts and is over-produced in adenocarcinomas and other cancers. We have recently shown that QSOX1 is required for incorporation of particular laminin isoforms into the extracellular matrix (ECM) of cultured fibroblasts and, as a consequence, for tumor cell adhesion to and ...
DOI:
10.1016/j.jmb.2013.07.011

3. A Novel Method to Analyze Nucleocytoplasmic Transport In Vivo by Using Short Peptide Tags

Author:
Wimmer, Cornelius; Platzer, Stephanie; Hillen, Wolfgang; Klotzsche, Marcus
Source:
Journal of Molecular Biology 2013 v.425 pp. 1839-1845
ISSN:
0022-2836
Subject:
green fluorescent protein; glucocorticoid receptors; humans; cell physiology; nucleocytoplasmic transport; reporter genes; screening
Abstract:
... Regulated nucleocytoplasmic transport is of vital importance for maintaining the physiology of the cell, and disturbed nucleocytoplasmic shuttling of certain proteins has been found in a variety of diseases including cancer. The most frequently used procedure to analyze those processes is to fuse the protein of interest to a fluorescent protein such as GFP (green fluorescent protein)—a technique t ...
DOI:
10.1016/j.jmb.2013.02.007
PubMed:
23416199

4. A Personal Reflection on the Replicon Theory: From R1 Plasmid to Replication Timing Regulation in Human Cells

Author:
Masai, Hisao
Source:
Journal of Molecular Biology 2013 v.425 pp. 4663-4672
ISSN:
0022-2836
Subject:
DNA replication; eukaryotic cells; evolution; genome; human diseases; humans; plasmids; replicon
Abstract:
... Fifty years after the Replicon Theory was originally presented, detailed mechanistic insight into prokaryotic replicons has been obtained and rapid progress is being made to elucidate the more complex regulatory mechanisms of replicon regulation in eukaryotic cells. Here, I present my personal perspectives on how studies of model replicons have contributed to our understanding of the basic mechani ...
DOI:
10.1016/j.jmb.2013.03.039
PubMed:
23579064

5. Arranged Sevenfold: Structural Insights into the C-Terminal Oligomerization Domain of Human C4b-Binding Protein

Author:
Hofmeyer, Thomas; Schmelz, Stefan; Degiacomi, Matteo T.; Dal Peraro, Matteo; Daneschdar, Matin; Scrima, Andrea; van den Heuvel, Joop; Heinz, Dirk W.; Kolmar, Harald
Source:
Journal of Molecular Biology 2013 v.425 pp. 1302-1317
ISSN:
0022-2836
Subject:
apoptosis; complement; crystal structure; disulfide bonds; electrostatic interactions; humans; immune response; innate immunity; lectins; microorganisms; pathogens
Abstract:
... The complement system as a major part of innate immunity is the first line of defense against invading microorganisms. Orchestrated by more than 60 proteins, its major task is to discriminate between host cells and pathogens and to initiate immune response. Additional recognition of necrotic or apoptotic cells demands a fine-tune regulation of this powerful system. C4b-binding protein (C4BP) is th ...
DOI:
10.1016/j.jmb.2012.12.017
PubMed:
23274142

6. Building a Genome Analysis Pipeline to Predict Disease Risk and Prevent Disease

Author:
Bromberg, Y.
Source:
Journal of Molecular Biology 2013 v.425 pp. 3993-4005
ISSN:
0022-2836
Subject:
risk; transcriptomics; medicine; humans; phenotype; genome; mutation; methodology; prediction
Abstract:
... Reduced costs and increased speed and accuracy of sequencing can bring the genome-based evaluation of individual disease risk to the bedside. While past efforts have identified a number of actionable mutations, the bulk of genetic risk remains hidden in sequence data. The biggest challenge facing genomic medicine today is the development of new techniques to predict the specifics of a given human ...
DOI:
10.1016/j.jmb.2013.07.038
PubMed:
23928561

7. Combinatorial Design of an Anticalin Directed against the Extra-Domain B for the Specific Targeting of Oncofetal Fibronectin

Author:
Gebauer, Michaela; Schiefner, André; Matschiner, Gabriele; Skerra, Arne
Source:
Journal of Molecular Biology 2013 v.425 pp. 780-802
ISSN:
0022-2836
Subject:
Escherichia coli; bacteriophages; crystal structure; drugs; enzyme-linked immunosorbent assay; epitopes; extracellular matrix; fibronectins; fluorescence microscopy; humans; image analysis; screening; therapeutics
Abstract:
... The oncofetal isoform of the extracellular matrix protein fibronectin (Fn), which carries the extra-domain B (ED-B) and is exclusively expressed in neovasculature, has gained interest for tumor diagnosis and therapy using engineered antibody fragments. We have employed the human lipocalin 2 (Lcn2) as a small and robust non-immunoglobulin scaffold to select ED-B-specific Anticalins from a new advan ...
DOI:
10.1016/j.jmb.2012.12.004
PubMed:
23238252

8. Conformational Analysis of StrH, the Surface-Attached exo-β-d-N-Acetylglucosaminidase from Streptococcus pneumoniae

Author:
Pluvinage, Benjamin; Chitayat, Seth; Ficko-Blean, Elizabeth; Abbott, D. Wade; Kunjachen, Jobby Maroor; Grondin, Julie; Spencer, Holly L.; Smith, Steven P.; Boraston, Alisdair B.
Source:
Journal of Molecular Biology 2013 v.425 pp. 334-349
ISSN:
0022-2836
Subject:
Streptococcus pneumoniae; X-radiation; X-ray diffraction; bacteria; beta-galactosidase; humans; models; pathogens; polysaccharides; sialidase; surface proteins; virulence
Abstract:
... Streptococcus pneumoniae is a serious human pathogen that presents on its surface numerous proteins involved in the host–bacterium interaction. The carbohydrate-active enzymes are particularly well represented among these surface proteins, and many of these are known virulence factors, highlighting the importance of carbohydrate processing by this pathogen. StrH is a surface-attached exo-β-d-N-ace ...
DOI:
10.1016/j.jmb.2012.11.005
PubMed:
23154168

9. Crystal Structure of the Plasmodium falciparum Thioredoxin Reductase–Thioredoxin Complex

Author:
Fritz-Wolf, Karin; Jortzik, Esther; Stumpf, Michaela; Preuss, Janina; Iozef, Rimma; Rahlfs, Stefan; Becker, Katja
Source:
Journal of Molecular Biology 2013 v.425 pp. 3446-3460
ISSN:
0022-2836
Subject:
Plasmodium falciparum; amino acids; binding sites; catalytic activity; crystal structure; drugs; homeostasis; humans; parasites
Abstract:
... Over the last decades, malaria parasites have been rapidly developing resistance against antimalarial drugs, which underlines the need for novel drug targets. Thioredoxin reductase (TrxR) is crucially involved in redox homeostasis and essential for Plasmodium falciparum. Here, we report the first crystal structure of P. falciparum TrxR bound to its substrate thioredoxin 1. Upon complex formation, ...
DOI:
10.1016/j.jmb.2013.06.037
PubMed:
23845423

10. Crystal Structures of the Free and Ligand-Bound FK1–FK2 Domain Segment of FKBP52 Reveal a Flexible Inter-Domain Hinge

Author:
Bracher, Andreas; Kozany, Christian; Hähle, Andreas; Wild, Philipp; Zacharias, Martin; Hausch, Felix
Source:
Journal of Molecular Biology 2013 v.425 pp. 4134-4144
ISSN:
0022-2836
Subject:
crystal structure; humans; ion channels; ligands; neoplasms; neurons; peptidylprolyl isomerase; phosphorylation; steroid hormone receptors
Abstract:
... The human Hsp90 co-chaperone FKBP52 belongs to the family of FK506-binding proteins, which act as peptidyl-prolyl isomerases. FKBP52 specifically enhances the signaling of steroid hormone receptors, modulates ion channels and regulates neuronal outgrowth dynamics. In turn, small-molecule ligands of FKBP52 have been suggested as potential neurotrophic or anti-prostate cancer agents. The usefulness ...
DOI:
10.1016/j.jmb.2013.07.041

11. Design of Synthetic Autonomous VH Domain Libraries and Structural Analysis of a VH Domain Bound to Vascular Endothelial Growth Factor

Author:
Ma, Xiaolei; Barthelemy, Pierre A.; Rouge, Lionel; Wiesmann, Christian; Sidhu, Sachdev S.
Source:
Journal of Molecular Biology 2013 v.425 pp. 2247-2259
ISSN:
0022-2836
Subject:
epitopes; humans; mice; vascular endothelial growth factor receptors; vascular endothelial growth factors
Abstract:
... We compared the capacity of an autonomous heavy chain variable (VH) domain (VH-B1a) to support diversity within its antigen-binding site relative to the conventional antigen-binding fragment (Fab) from which it was derived. We find that VH-B1a can tolerate significant diversity within all three complementarity-determining regions (CDRs) and also within framework 3, and thus, VH-B1a and the Fab are ...
DOI:
10.1016/j.jmb.2013.03.020
PubMed:
23507309

12. Dissecting the Molecular Mechanism of IVIg Therapy: The Interaction between Serum IgG and DC-SIGN is Independent of Antibody Glycoform or Fc Domain

Author:
Yu, Xiaojie; Vasiljevic, Snezana; Mitchell, Daniel A.; Crispin, Max; Scanlan, Christopher N.
Source:
Journal of Molecular Biology 2013 v.425 pp. 1253-1258
ISSN:
0022-2836
Subject:
anti-inflammatory activity; immunoglobulin G; X-ray diffraction; blood serum; humans; intravenous injection; lectins; models; cytokines; mice; adhesion; polysaccharides; receptors
Abstract:
... Intravenous immunoglobulin (IVIg) therapy is used to treat a wide range of autoimmune conditions and consists of pooled immunoglobulin G (IgG) from healthy donors. The immunosuppressive effects of IVIg are, in part, attributed to terminal α2,6-linked sialic acid residues on the N-linked glycans of the IgG Fc (fragment crystallizable) domain. This α2,6-sialylated Fc (sFc) has been reported to bind ...
DOI:
10.1016/j.jmb.2013.02.006
PubMed:
23416198

13. From Simple Bacterial and Archaeal Replicons to Replication N/U-Domains

Author:
Hyrien, Olivier; Rappailles, Aurélien; Guilbaud, Guillaume; Baker, Antoine; Chen, Chun-Long; Goldar, Arach; Petryk, Nataliya; Kahli, Malik; Ma, Emilie; d'Aubenton-Carafa, Yves; Audit, Benjamin; Thermes, Claude; Arneodo, Alain
Source:
Journal of Molecular Biology 2013 v.425 pp. 4673-4689
ISSN:
0022-2836
Subject:
bacteria; chromatin; evolution; genome; germ cells; humans; replicon
Abstract:
... The Replicon Theory proposed 50years ago has proven to apply for replicons of the three domains of life. Here, we review our knowledge of genome organization into single and multiple replicons in bacteria, archaea and eukarya. Bacterial and archaeal replicator/initiator systems are quite specific and efficient, whereas eukaryotic replicons show degenerate specificity and efficiency, allowing for c ...
DOI:
10.1016/j.jmb.2013.09.021
PubMed:
24095859

14. Genomes and G-Quadruplexes: For Better or for Worse

Author:
Tarsounas, Madalena; Tijsterman, Marcel
Source:
Journal of Molecular Biology 2013 v.425 pp. 4782-4789
ISSN:
0022-2836
Subject:
DNA replication; cell proliferation; chromosome segregation; epigenetics; eukaryotic cells; gene expression; genome; humans; inheritance (genetics); metastasis; mutation; neoplasms; single-stranded DNA; telomeres
Abstract:
... Genomic integrity is crucial for correct chromosome segregation and physiological rates of cell proliferation. Mutations, deletions and translocations, hallmarks of human tumors, drive the aberrant proliferation and metastatic behavior of cancer cells. These chromosomal rearrangements often occur at genomic sites susceptible to breakage during DNA replication, including regions with G-quadruplex ( ...
DOI:
10.1016/j.jmb.2013.09.026
PubMed:
24076189

15. Hemoglobin Allostery: New Views on Old Players

Author:
Miele, Adriana Erica; Bellelli, Andrea; Brunori, Maurizio
Source:
Journal of Molecular Biology 2013 v.425 pp. 1515-1526
ISSN:
0022-2836
Subject:
biochemical pathways; correlation; energy; enzymes; hemoglobin; humans; models; natural selection; oxygen; thermodynamics; trout
Abstract:
... Proteins are dynamic molecular machines whose structure and function are modulated by environmental perturbations and natural selection. Allosteric regulation, discovered in 1963 as a novel molecular mechanism of enzymatic adaptation [Monod, Changeux & Jacob (1963). J. Mol. Biol.6, 306–329], seems to be the leit motiv of enzymes and metabolic pathways, enabling fine and quick responses toward exte ...
DOI:
10.1016/j.jmb.2012.12.018
PubMed:
23274140

16. Hidden Allostery in Human Glutathione Transferase P1-1 Unveiled by Unnatural Amino Acid Substitutions and Inhibition Studies

Author:
Hegazy, Usama M.; Musdal, Yaman; Mannervik, Bengt
Source:
Journal of Molecular Biology 2013 v.425 pp. 1509-1514
ISSN:
0022-2836
Subject:
alkylation; amino acids; catalytic activity; enzyme activity; ethacrynic acid; glutathione transferase; humans; mutants
Abstract:
... Conventional steady-state kinetic studies of the dimeric human glutathione transferase (GST) P1-1 do not reveal obvious deviations from Michaelis–Menten behavior. By contrast, engineering of the key residue Y50 of the lock-and-key motif in the subunit interface reveals allosteric properties of the enzyme. The low-activity mutant Y50C, characterized by 150-fold decreased kcat and 300-fold increased ...
DOI:
10.1016/j.jmb.2013.01.038
PubMed:
23399543

17. Impacts of Variation in the Human Genome on Gene Regulation

Author:
Haraksingh, Rajini R.; Snyder, Michael P.
Source:
Journal of Molecular Biology 2013 v.425 pp. 3970-3977
ISSN:
0022-2836
Subject:
DNA; RNA; gene expression; genes; genetic variation; genomics; humans; models; sequence analysis; transcriptomics
Abstract:
... Recent advances in fast and inexpensive DNA sequencing have enabled the extensive study of genomic and transcriptomic variation in humans. Human genomic variation is composed of sequence and structural changes including single-nucleotide and multinucleotide variants, short insertions or deletions (indels), larger copy number variants, and similarly sized copy neutral inversions and translocations. ...
DOI:
10.1016/j.jmb.2013.07.015
PubMed:
23871684

18. Mechanism of Action and In Vivo Efficacy of a Human-Derived Antibody against Staphylococcus aureus α-Hemolysin

Author:
Foletti, Davide; Strop, Pavel; Shaughnessy, Lee; Hasa-Moreno, Adela; Casas, Meritxell Galindo; Russell, Marcella; Bee, Christine; Wu, Si; Pham, Amber; Zeng, Zhilan; Pons, Jaume; Rajpal, Arvind; Shelton, Dave
Source:
Journal of Molecular Biology 2013 v.425 pp. 1641-1654
ISSN:
0022-2836
Subject:
Staphylococcus aureus; animal models; antibiotics; antibodies; bacteremia; blood serum; crystal structure; humans; immune system; mechanism of action; multiple drug resistance; neutralization; plasma membrane; pneumonia; therapeutics
Abstract:
... The emergence and spread of multi-drug-resistant strains of Staphylococcus aureus in hospitals and in the community emphasize the urgency for the development of novel therapeutic interventions. Our approach was to evaluate the potential of harnessing the human immune system to guide the development of novel therapeutics. We explored the role of preexisting antibodies against S. aureus α-hemolysin ...
DOI:
10.1016/j.jmb.2013.02.008
PubMed:
23416200

19. Metastasis-Promoting Anterior Gradient 2 Protein Has a Dimeric Thioredoxin Fold Structure and a Role in Cell Adhesion

Author:
Patel, Pryank; Clarke, Christopher; Barraclough, Dong Liu; Jowitt, Thomas Adam; Rudland, Philip Spencer; Barraclough, Roger; Lian, Lu-Yun
Source:
Journal of Molecular Biology 2013 v.425 pp. 929-943
ISSN:
0022-2836
Subject:
adhesion; amphibians; cell adhesion; dimerization; endoplasmic reticulum; humans; metastasis; nuclear magnetic resonance spectroscopy
Abstract:
... Anterior gradient 2 (AGR2) is a normal endoplasmic reticulum protein that has two important abnormal functions, amphibian limb regeneration and human cancer metastasis promotion. These normal intracellular and abnormal extracellular roles can be attributed to the multidomain structure of AGR2. The NMR structure shows that AGR2 consists of an unstructured N-terminal region followed by a thioredoxin ...
DOI:
10.1016/j.jmb.2012.12.009
PubMed:
23274113

20. Molecular Mechanism of Peroxisome Proliferator-Activated Receptor α Activation by WY14643: a New Mode of Ligand Recognition and Receptor Stabilization

Author:
Bernardes, Amanda; Souza, Paulo C.T.; Muniz, João R.C.; Ricci, Clarisse G.; Ayers, Stephen D.; Parekh, Nili M.; Godoy, André S.; Trivella, Daniela B.B.; Reinach, Peter; Webb, Paul; Skaf, Munir S.; Polikarpov, Igor
Source:
Journal of Molecular Biology 2013 v.425 pp. 2878-2893
ISSN:
0022-2836
Subject:
binding capacity; cornea; crystal structure; drugs; glucose; human diseases; humans; hyperlipidemia; lipid metabolism; models; molecular dynamics; receptors; transcription factors
Abstract:
... Peroxisome proliferator-activated receptors (PPARs) are members of a superfamily of nuclear transcription factors. They are involved in mediating numerous physiological effects in humans, including glucose and lipid metabolism. PPARα ligands effectively treat dyslipidemia and have significant antiinflammatory and anti-atherosclerotic activities. These effects and their ligand-dependent activity ma ...
DOI:
10.1016/j.jmb.2013.05.010
PubMed:
23707408

21. New Insights into Replication Clamp Unloading

Author:
Ulrich, Helle D.
Source:
Journal of Molecular Biology 2013 v.425 pp. 4727-4732
ISSN:
0022-2836
Subject:
DNA; chromatin; genome; humans; proliferating cell nuclear antigen; yeasts
Abstract:
... The sliding clamp protein proliferating cell nuclear antigen (PCNA) is situated at the core of the eukaryotic replisome, where it acts as an interaction scaffold for numerous replication and repair factors and coordinates DNA transactions ranging from Okazaki fragment maturation to chromatin assembly and mismatch repair. PCNA is loaded onto DNA by a dedicated complex, the replication factor C, who ...
DOI:
10.1016/j.jmb.2013.05.003
PubMed:
23688817

22. Oligomeric States along the Folding Pathways of β2-Microglobulin: Kinetics, Thermodynamics, and Structure

Author:
Rennella, E.; Cutuil, T.; Schanda, P.; Ayala, I.; Gabel, F.; Forge, V.; Corazza, A.; Esposito, G.; Brutscher, B.
Source:
Journal of Molecular Biology 2013 v.425 pp. 2722-2736
ISSN:
0022-2836
Subject:
X-radiation; amyloid; dimerization; human diseases; humans; models; nuclear magnetic resonance spectroscopy; thermodynamics
Abstract:
... The transition of proteins from their soluble functional state to amyloid fibrils and aggregates is associated with the onset of several human diseases. Protein aggregation often requires some structural reshaping and the subsequent formation of intermolecular contacts. Therefore, the study of the conformation of excited protein states and their ability to form oligomers is of primary importance f ...
DOI:
10.1016/j.jmb.2013.04.028
PubMed:
23648836

23. Progress in Detecting Genetic Alterations and Their Association with Human Disease

Author:
Schwartz, Charles E.; Chen, Chin-Fu
Source:
Journal of Molecular Biology 2013 v.425 pp. 3914-3918
ISSN:
0022-2836
Subject:
equipment; genes; high-throughput nucleotide sequencing; human diseases; humans; mutation; patients
Abstract:
... The completion of the Human Genome Project provided a reference sequence to which researchers could compare sequences from individual patients in the hope of identifying disease-causing mutations. However, this still necessitated candidate gene testing or a very limited screen of multiple genes using Sanger sequencing. With the advent of high-throughput Sanger sequencing, it became possible to scr ...
DOI:
10.1016/j.jmb.2013.07.023
PubMed:
23876707

24. Protein Conformational Change Delayed by Steric Hindrance from an N-Linked Glycan

Author:
Bager, René; Johansen, Jesper S.; Jensen, Jan K.; Stensballe, Allan; Jendroszek, Agnieszka; Buxbom, Linette; Sørensen, Hans Peter; Andreasen, Peter A.
Source:
Journal of Molecular Biology 2013 v.425 pp. 2867-2877
ISSN:
0022-2836
Subject:
Danio rerio; X-ray diffraction; fish; glycosylation; humans; plasminogen activator; polysaccharides; protein conformation
Abstract:
... Very few studies have attributed a direct, active, functional role to N-linked glycans. We describe here an N-linked glycan with a unique role for maintaining the active conformation of a protein of the serpin family. The distinguishing feature of serpins is the “stressed-to-relaxed” transition, in which the reactive center loop inserts as a β-strand into the central β-sheet A. This transition for ...
DOI:
10.1016/j.jmb.2013.05.007
PubMed:
23702291

25. Serum-Dependent Enhancement of Coxsackievirus B4-Induced Production of IFNα, IL-6 and TNFα by Peripheral Blood Mononuclear Cells

Author:
Alidjinou, Enagnon Kazali; Sané, Famara; Engelmann, Ilka; Hober, Didier
Source:
Journal of Molecular Biology 2013 v.425 pp. 5020-5031
ISSN:
0022-2836
Subject:
RNA; antibodies; antiserum; blood serum; enzyme-linked immunosorbent assay; humans; immunoglobulin G; interleukin-10; interleukin-12; interleukin-6; mononuclear leukocytes; quantitative polymerase chain reaction; tumor necrosis factor-alpha; viral load; viruses
Abstract:
... Only a few reports have been published on the interactions between Coxsackievirus B4 (CVB4) and human peripheral blood mononuclear cells (PBMC) but have not been extensively documented. Human serum containing non-neutralizing anti-CVB4 antibodies increased CVB4-induced synthesis of IFNα by PBMC. In this study, we determined if CVB4 and human serum have the ability to activate inflammatory cytokine ...
DOI:
10.1016/j.jmb.2013.10.008
PubMed:
24120940

26. Structural Basis for the Interaction of Human β-Defensin 6 and Its Putative Chemokine Receptor CCR2 and Breast Cancer Microvesicles

Author:
De Paula, V.S.; Gomes, N.S.F.; Lima, L.G.; Miyamoto, C.A.; Monteiro, R.Q.; Almeida, F.C.L.; Valente, A.P.
Source:
Journal of Molecular Biology 2013 v.425 pp. 4479-4495
ISSN:
0022-2836
Subject:
nuclear magnetic resonance spectroscopy; chemoattractants; humans; CCR2 receptor; adaptive immunity; inflammation; models; antineoplastic agents; amino acids; binding sites; anti-infective properties; beta chemokines; molecular conformation; breast neoplasms
Abstract:
... Human β-defensins (hBDs) are believed to function as alarm molecules that stimulate the adaptive immune system when a threat is present. In addition to its antimicrobial activity, defensins present other activities such as chemoattraction of a range of different cell types to the sites of inflammation. We have solved the structure of the hBD6 by NMR spectroscopy that contains a conserved β-defensi ...
DOI:
10.1016/j.jmb.2013.08.001

27. Structure of Internalin InlK from the Human Pathogen Listeria monocytogenes

Author:
Neves, David; Job, Viviana; Dortet, Laurent; Cossart, Pascale; Dessen, Andréa
Source:
Journal of Molecular Biology 2013 v.425 pp. 4520-4529
ISSN:
0022-2836
Subject:
Listeria monocytogenes; adhesion; autophagy; bacteria; humans; pathogens; virulence
Abstract:
... Listeria monocytogenes is a human pathogen that employs a wide variety of virulence factors in order to adhere to, invade, and replicate within target cells. Internalins play key roles in processes ranging from adhesion to receptor recognition and are thus essential for infection. Recently, InlK, a surface-associated internalin, was shown to be involved in Listeria's ability to escape from autopha ...
DOI:
10.1016/j.jmb.2013.08.010

28. Structures of Intermediates along the Catalytic Cycle of Terminal Deoxynucleotidyltransferase: Dynamical Aspects of the Two-Metal Ion Mechanism

Author:
Gouge, Jérôme; Rosario, Sandrine; Romain, Félix; Beguin, Pierre; Delarue, Marc
Source:
Journal of Molecular Biology 2013 v.425 pp. 4334-4352
ISSN:
0022-2836
Subject:
manganese; DNA damage; cobalt; humans; T-lymphocytes; reaction kinetics; sugars; DNA; zinc; models; nucleotides; immunoglobulins; DNA repair; active sites; receptors; DNA-directed DNA polymerase; catalytic activity; metal ions; X-radiation
Abstract:
... Terminal deoxynucleotidyltransferase (Tdt) is a non-templated eukaryotic DNA polymerase of the polX family that is responsible for the random addition of nucleotides at the V(D)J junctions of immunoglobulins and T-cell receptors. Here we describe a series of high-resolution X-ray structures that mimic the pre-catalytic state, the post-catalytic state and a competent state that can be transformed i ...
DOI:
10.1016/j.jmb.2013.07.009

29. Substrate Specificity and Oligomerization of Human GMP Synthetase

Author:
Welin, Martin; Lehtiö, Lari; Johansson, Andreas; Flodin, Susanne; Nyman, Tomas; Trésaugues, Lionel; Hammarström, Martin; Gräslund, Susanne; Nordlund, Pär
Source:
Journal of Molecular Biology 2013 v.425 pp. 4323-4333
ISSN:
0022-2836
Subject:
ammonia; bacterial proteins; crystal structure; dimerization; glutaminase; glutamine; guanine; guanosine monophosphate; humans; immunosuppressive agents; ligases; metabolism; neoplasms; oligomerization; substrate specificity; xanthine
Abstract:
... Guanine monophosphate (GMP) synthetase is a bifunctional two-domain enzyme. The N-terminal glutaminase domain generates ammonia from glutamine and the C-terminal synthetase domain aminates xanthine monophosphate (XMP) to form GMP. Mammalian GMP synthetases (GMPSs) contain a 130-residue-long insert in the synthetase domain in comparison to bacterial proteins. We report here the structure of a eukar ...
DOI:
10.1016/j.jmb.2013.06.032

30. Targeted Methylation and Gene Silencing of VEGF-A in Human Cells by Using a Designed Dnmt3a–Dnmt3L Single-Chain Fusion Protein with Increased DNA Methylation Activity

Author:
Siddique, Abu Nasar; Nunna, Suneetha; Rajavelu, Arumugam; Zhang, Yingying; Jurkowska, Renata Z.; Reinhardt, Richard; Rots, Marianne G.; Ragozin, Sergey; Jurkowski, Tomasz P.; Jeltsch, Albert
Source:
Journal of Molecular Biology 2013 v.425 pp. 479-491
ISSN:
0022-2836
Subject:
DNA; DNA methylation; amino acids; catalytic activity; cell growth; endothelial cells; enzymes; gene silencing; genes; humans; proteins; vascular endothelial growth factor A
Abstract:
... The C-terminal domain of the Dnmt3a de novo DNA methyltransferase (Dnmt3a-C) forms a complex with the C-terminal domain of Dnmt3L, which stimulates its catalytic activity. We generated and characterized single-chain (sc) fusion proteins of both these domains with linker lengths between 16 and 30 amino acid residues. The purified sc proteins showed about 10-fold higher DNA methylation activities th ...
DOI:
10.1016/j.jmb.2012.11.038
PubMed:
23220192

31. The Discovery, Engineering and Characterisation of a Highly Potent Anti-Human IL-13 Fab Fragment Designed for Administration by Inhalation

Author:
Lightwood, Daniel; O'Dowd, Victoria; Carrington, Bruce; Veverka, Vaclav; Carr, Mark D.; Tservistas, Markus; Henry, Alistair J.; Smith, Bryan; Tyson, Kerry; Lamour, Sabrina; Sarkar, Kaushik; Turner, Alison; Lawson, Alastair D.; Bourne, Tim; Gozzard, Neil; Palframan, Roger
Source:
Journal of Molecular Biology 2013 v.425 pp. 577-593
ISSN:
0022-2836
Subject:
atomization; binding capacity; breathing; epitope mapping; genes; humans; immunoglobulin G; in vitro studies; interleukin-13; intranasal administration; neutralization; nuclear magnetic resonance spectroscopy
Abstract:
... We describe the discovery, engineering and characterisation of a highly potent anti-human interleukin (IL)-13 Fab fragment designed for administration by inhalation. The lead candidate molecule was generated via a novel antibody discovery process, and the selected IgG variable region genes were successfully humanised and reformatted as a human IgG γ1 Fab fragment. Evaluation of the biophysical pro ...
DOI:
10.1016/j.jmb.2012.11.036
PubMed:
23219467

32. The Human Specialized DNA Polymerases and Non-B DNA: Vital Relationships to Preserve Genome Integrity

Author:
Boyer, Anne-Sophie; Grgurevic, Srdana; Cazaux, Christophe; Hoffmann, Jean-Sébastien
Source:
Journal of Molecular Biology 2013 v.425 pp. 4767-4781
ISSN:
0022-2836
Subject:
DNA; DNA helicases; DNA replication; cell division; genome; humans; repetitive sequences
Abstract:
... In addition to the canonical right-handed double helix, DNA molecule can adopt several other non-B DNA structures. Readily formed in the genome at specific DNA repetitive sequences, these secondary conformations present a distinctive challenge for progression of DNA replication forks. Impeding normal DNA synthesis, cruciforms, hairpins, H DNA, Z DNA and G4 DNA considerably impact the genome stabil ...
DOI:
10.1016/j.jmb.2013.09.022
PubMed:
24095858

33. Three-Dimensional Structure and Biophysical Characterization of Staphylococcus aureus Cell Surface Antigen–Manganese Transporter MntC

Author:
Gribenko, Alexey; Mosyak, Lidia; Ghosh, Sharmistha; Parris, Kevin; Svenson, Kristine; Moran, Justin; Chu, Ling; Li, Sheng; Liu, Tong; Woods, Virgil L.; Jansen, Kathrin U.; Green, Bruce A.; Anderson, Annaliesa S.; Matsuka, Yury V.
Source:
Journal of Molecular Biology 2013 v.425 pp. 3429-3445
ISSN:
0022-2836
Subject:
Staphylococcus aureus; Staphylococcus epidermidis; X-ray diffraction; animal models; antigens; clinical trials; differential scanning calorimetry; humans; manganese; mass spectrometry; mice; pathogens; protein structure; titration
Abstract:
... MntC is a metal-binding protein component of the Mn2+-specific mntABC transporter from the pathogen Staphylococcus aureus. The protein is expressed during the early stages of infection and was proven to be effective at reducing both S. aureus and Staphylococcus epidermidis infections in a murine animal model when used as a vaccine antigen. MntC is currently being tested in human clinical trials as ...
DOI:
10.1016/j.jmb.2013.06.033
PubMed:
23827136

34. Type 2 Ryanodine Receptor Domain A Contains a Unique and Dynamic α-Helix That Transitions to a β-Strand in a Mutant Linked with a Heritable Cardiomyopathy

Author:
Amador, Fernando J.; Kimlicka, Lynn; Stathopulos, Peter B.; Gasmi-Seabrook, Geneviève M.C.; MacLennan, David H.; Van Petegem, Filip; Ikura, Mitsuhiko
Source:
Journal of Molecular Biology 2013 v.425 pp. 4034-4046
ISSN:
0022-2836
Subject:
X-radiation; X-ray diffraction; calcium; cardiomyopathy; exons; humans; hypothermia; microscopy; mutants; mutation; nuclear magnetic resonance spectroscopy; ryanodine receptors; sarcoplasmic reticulum
Abstract:
... Ryanodine receptors (RyRs) are large tetrameric calcium (Ca2+) release channels found on the sarcoplasmic reticulum that respond to dihydropyridine receptor activity through a direct conformational interaction and/or indirect Ca2+ sensitivity, propagating sarcoplasmic reticulum luminal Ca2+ release in the process of excitation–contraction coupling. There are three human RyR subtypes, and several d ...
DOI:
10.1016/j.jmb.2013.08.015
PubMed:
23978697

35. Why Are There So Many Diverse Replication Machineries?

Author:
Forterre, Patrick
Source:
Journal of Molecular Biology 2013 v.425 pp. 4714-4726
ISSN:
0022-2836
Subject:
Archaea; DNA; DNA replication; DNA viruses; DNA-directed DNA polymerase; RNA; bacteria; biosynthesis; eukaryotic cells; humans; models; molecular biology; operon; proteins; replicon; telomeres; virus replication; yeasts
Abstract:
... The replicon model has initiated a major research line in molecular biology: the study of DNA replication mechanisms. Until now, the majority of studies have focused on a limited set of model organisms, mainly from Bacteria or Opisthokont eukaryotes (human, yeasts) and a few viral systems. However, molecular evolutionists have shown that the living world is more complex and diverse than believed w ...
DOI:
10.1016/j.jmb.2013.09.032
PubMed:
24075868