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Thrombin-like enzymes from snake venom: Structural characterization and mechanism of action

Ullah, Anwar, Masood, Rehana, Ali, Ijaz, Ullah, Kifayat, Ali, Hamid, Akbar, Haji, Betzel, Christian
International journal of biological macromolecules 2018 v.114 pp. 788-811
active sites, coagulants, coagulation, crystal structure, databases, fibrinolysis, heart failure, humans, mechanism of action, nervous system diseases, platelet aggregation, sequence analysis, snake venoms, stroke, substrate specificity, suramin, therapeutics, thrombosis, trypsin
Snake venom thrombin-like enzymes (SVTLEs) constitute the major portion (10–24%) of snake venom and these are the second most abundant enzymes present in the crude venom. During envenomation, these enzymes had shown prominently the various pathological effects, such as disturbance in hemostatic system, fibrinogenolysis, fibrinolysis, platelet aggregation, thrombosis, neurologic disorders, activation of coagulation factors, coagulant, procoagulant etc. These enzymes also been used as a therapeutic agent for the treatment of various diseases such as congestive heart failure, ischemic stroke, thrombotic disorders etc. Although the crystal structures of five SVTLEs are available in the Protein Data Bank (PDB), there is no single article present in the literature that has described all of them. The current work describes the structural aspects, structure-based mechanism of action, processing and inhibition of these enzymes. The sequence analysis indicates that these enzymes show a high sequence identity (57–85%) with each other and low sequence identity with trypsin (36–43%), human alpha-thrombin (29–36%) and other snake venom serine proteinases (57–85%). Three-dimensional structural analysis indicates that the loops surrounding the active site are variable both in amino acids composition and length that may convey variable substrate specificity to these enzymes. The surface charge distributions also vary in these enzymes. Docking analysis with suramin shows that this inhibitor preferably binds to the C-terminal region of these enzymes and causes the destabilization of their three-dimensional structure.