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1hdt
From Proteopedia
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STRUCTURE OF A RETRO-BINDING PEPTIDE INHIBITOR COMPLEXED WITH HUMAN ALPHA-THROMBIN
Contents |
Overview
The crystallographic structure of the ternary complex between human, alpha-thrombin, hirugen and the peptidyl inhibitor Phe-alloThr-Phe-O-CH3, which is acylated at its N terminus with 4-guanidino butanoic acid, (BMS-183507), has been determined at 2.6 A resolution. The structure, reveals a unique "retro-binding" mode for this tripeptide active site, inhibitor. The inhibitor binds with its alkyl-guanidine moiety in the, primary specificity pocket and its two phenyl rings occupying the, hydrophobic proximal and distal pockets of the thrombin active site. In, this arrangement the backbone of the tripeptide forms a parallel, beta-strand to the thrombin main-chain at the binding site. This is, opposite to the orientation of the natural substrate, fibrinogen, and all, the small active site-directed thrombin inhibitors whose bound structures, have been previously reported. BMS-183507 is the first synthetic inhibitor, proved to bind in a retro-binding fashion to thrombin, in a fashion, similar to that of the N-terminal residues of the natural inhibitor, hirudin. Furthermore, this new potent thrombin inhibitor (Ki = 17.2 nM) is, selective for thrombin over other serine proteases tested and may be a, template to be considered in designing hirudin-based thrombin inhibitors, with interactions at the specificity pocket.
Disease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this Structure
1HDT is a Single protein structure of sequence from Homo sapiens with SO3 and CH3 as ligands. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.
Reference
Structure of a retro-binding peptide inhibitor complexed with human alpha-thrombin., Tabernero L, Chang CY, Ohringer SL, Lau WF, Iwanowicz EJ, Han WC, Wang TC, Seiler SM, Roberts DG, Sack JS, J Mol Biol. 1995 Feb 10;246(1):14-20. PMID:7853394
Page seeded by OCA on Mon Nov 12 17:16:41 2007
