1kug | pdb_00001kug
Crystal Structure of a Taiwan Habu Venom Metalloproteinase complexed with its endogenous inhibitor pENW
Structural highlights
Function[VM2T3_PROMU] Snake venom metalloproteinase TM-3: fibrin(ogen)olytic protease which cleaves the Aalpha chain of fibrinogen (FGA) first followed by the Bbeta chain (FGB) and shows relatively low activity on the gamma chain (FGG).[1] [2] Disintegrin trimucrin: inhibits platelet aggregation induced by ADP, thrombin, platelet-activating factor and collagen. Acts by inhibiting fibrinogen interaction with platelet receptors GPIIb/GPIIIa (ITGA2B/ITGB3).[3] [4] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedVenoms from crotalid and viperid snakes contain several peptide inhibitors which regulate the proteolytic activities of their snake-venom metalloproteinases (SVMPs) in a reversible manner under physiological conditions. In this report, we describe the high-resolution crystal structures of a SVMP, TM-3, from Taiwan habu (Trimeresurus mucrosquamatus) cocrystallized with the endogenous inhibitors pyroGlu-Asn-Trp (pENW), pyroGlu-Gln-Trp (pEQW) or pyroGlu-Lys-Trp (pEKW). The binding of inhibitors causes some of the residues around the inhibitor-binding environment of TM-3 to slightly move away from the active-site center, and displaces two metal-coordinated water molecules by the C-terminal carboxylic group of the inhibitors. This binding adopts a retro-manner principally stabilized by four possible hydrogen bonds. The Trp indole ring of the inhibitors is stacked against the imidazole of His143 in the S-1 site of the proteinase. Results from the study of synthetic inhibitor analogues showed the primary specificity of Trp residue of the inhibitors at the P-1 site, corroborating the stacking effect observed in our structures. Furthermore, we have made a detailed comparison of our structures with the binding modes of other inhibitors including batimastat, a hydroxamate inhibitor, and a barbiturate derivative. It suggests a close correlation between the inhibitory activity of an inhibitor and its ability to fill the S-1 pocket of the proteinase. Our work may provide insights into the rational design of small molecules that bind to this class of zinc-metalloproteinases. Determinants of the inhibition of a Taiwan habu venom metalloproteinase by its endogenous inhibitors revealed by X-ray crystallography and synthetic inhibitor analogues.,Huang KF, Chiou SH, Ko TP, Wang AH Eur J Biochem. 2002 Jun;269(12):3047-56. PMID:12071970[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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