Thrombomodulin-independent activation of protein C and specificity of hemostatically active snake venom serine proteinases: crystal structures of native and inhibited Agkistrodon contortrix contortrix protein C activator.
Protein C activation initiated by the thrombin-thrombomodulin complex forms the major physiological anticoagulant pathway. Agkistrodon contortrix contortrix protein C activator, a glycosylated single-chain serine proteinase, activates protein C without relying on thrombomodulin. The crystal structures of native and inhibited Agkistrodon contortrix contortrix protein C activator determined at 1.65 and 1.54 A resolutions, respectively, indicate the pivotal roles played by the positively charged belt and the strategic positioning of the three carbohydrate moieties surrounding the catalytic site in protein C recognition, binding, and activation. Structural changes in the benzamidine-inhibited enzyme suggest a probable function in allosteric regulation for the anion-binding site located in the C-terminal extension, which is fully conserved in snake venom serine proteinases, that preferentially binds Cl(1-) instead of SO(4)(2-).
Murakami
Mário T
MT
Biochemistry and Structural Biology Group, Department of Physics, IBILCE/UNESP, São José do Rio Preto, SP 15054-000, Brazil.
Arni
Raghuvir K
RK
D017836:Agkistrodon / Q000235:genetics / Q000378:metabolism; D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000721:Ancrod / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001550:Benzamidines / Q000494:pharmacology; D020134:Catalytic Domain; D003435:Crotalid Venoms / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006487:Hemostasis; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011486:Protein C / Q000378:metabolism*; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D055672:Static Electricity; D018180:Thrombomodulin / Q000378:metabolism
C031442:Agkistrodon venoms; D001550:Benzamidines; D003435:Crotalid Venoms; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D011486:Protein C; D015842:Serine Proteinase Inhibitors; D018180:Thrombomodulin; C049647:snake venom protein C activator; D000721:Ancrod; C032157:benzamidine