tailieunhanh - Báo cáo Y học: Determinants of the inhibition of a Taiwan habu venom metalloproteinase by its endogenous inhibitors revealed by X-ray crystallography and synthetic inhibitor analogues

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). | Eur. J. Biochem. 269 3047-3056 2002 FEBS 2002 doi Determinants of the inhibition of a Taiwan habu venom metalloproteinase by its endogenous inhibitors revealed by X-ray crystallography and synthetic inhibitor analogues Kai-Fa Huang1 Shyh-Horng Chiou1 2 Tzu-Ping Ko1 and Andrew . Wang1 2 1Institute of Biological Chemistry Academia Sinica Taipei Taiwan 2Institute of Biochemical Sciences National Taiwan University Taipei Taiwan 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. hl this report we describe the high-resolution crystal structures of a SVMP TM-3 from Taiwan habu Trimeresurus mucro-squamatus 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. Th IS binding adopts a retro-manner principally stabilized by four possible hydrogen bonds. The Tip indole ring of the ứhi l--itors is stacked against the imidazole of His143 in the S 1 site of the proteinase. Re sl iks from die study ơi synthedc 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 myy poovide 1 m ighus ìnto die rational design of small molecules that bind

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