1kuk
Crystal Structure of a Taiwan Habu Venom Metalloproteinase complexed with pEKW.
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OverviewOverview
Venoms 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.
About this StructureAbout this Structure
1KUK is a Single protein structure of sequence from Protobothrops mucrosquamatus with as ligand. Active as Atrolysin E, with EC number 3.4.24.44 Full crystallographic information is available from OCA.
ReferenceReference
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
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