3bv9

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Template:STRUCTURE 3bv9

Structure of Thrombin Bound to the Inhibitor FM19

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Background: Novel pentapeptides called Thrombostatin FM compounds consisting mostly of D-isomers and unusual amino acids were prepared based upon the stable angiotensin converting enzyme breakdown product of bradykinin - RPPGF. Methods and Results: These peptides are direct thrombin inhibitors prolonging the thrombin clotting time, APTT, and PT at >/= 0.78, 1.6 and 1.6 muM, respectively. They competitively inhibit alpha-thrombin-induced cleavage of a chromogenic substrate at 4.4-8.2 muM. They do not significantly inhibit plasma kallikrein, FXIIa, FXIa, FIXa, FVIIa-TF, FXa, plasmin or cathepsin G. One form, FM19 [rOicPaF(p-Me)], blocks alpha-thrombin induced calcium flux in fibroblasts with an IC(50) of 6.9 +/- 1.2 muM. FM19 achieved 100% inhibition of threshold alpha- or gamma-thrombin-induced platelet aggregation at 8.4 +/- 4.7 muM and 16 +/- 4 muM, respectively. The crystal structure of thrombin in complex with FM19 shows that the N-terminal D-Arg retrobinds into the S1 pocket, its 2nd residue Oic interacts with His-57, Tyr-60a and Trp-60d, and its C-terminal p-methyl Phe engages thrombin's aryl binding site composed of Ile-174, Trp-215 and Leu-99. When administered intraperitoneal, intraduodenal, or orally to mice, FM19 prolongs thrombin clotting times and delays carotid artery thrombosis. Conclusion: FM19, a low affinity reversible direct thrombin inhibitor, might be useful as an add-on agent to address an unmet need in platelet inhibition in acute coronary syndromes in diabetics and others who with all current anti-platelet therapy still have reactive platelets.

Disease

Known disease associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]

About this Structure

3BV9 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Thrombostatin FM compounds: direct thrombin inhibitors - mechanism of action in vitro and in vivo., Nieman MT, Burke F, Warnock M, Zhou Y, Sweigart J, Chen A, Ricketts D, Lucchesi BR, Chen Z, Di Cera E, Hilfinger J, Kim JS, Mosberg HI, Schmaier AH, J Thromb Haemost. 2008 Feb 25;. PMID:18315550 Page seeded by OCA on Sun May 4 21:08:46 2008