1dit

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spinqualitylabelsall models 1dit, resolution 2.3Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

COMPLEX OF A DIVALENT INHIBITOR WITH THROMBIN

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

A new class of divalent thrombin inhibitors is described that contains an, alpha-keto-amide transition-state mimetic linking an active site binding, group and a group that binds to the fibrinogen-binding exosite. The X-ray, crystallographic structure of the most potent member of this new class, CVS995, shows many features in common with other divalent thrombin, inhibitors and clearly defines the transition-state-like binding of the, alpha-keto-amide group. The structure of the active site part of the, inhibitor shows a network of water molecules connecting both the, side-chain and backbone atoms of thrombin and the inhibitor. Direct, peptide analogues of the new transition-state-containing divalent thrombin, inhibitors were compared using in vitro assays of thrombin inhibition., There was no direct correlation between the binding constants of the, peptides and their alpha-keto-amide counterparts. The most potent, alpha-keto-amide inhibitor, CVS995, with a Ki = 1 pM, did not correspond, to the most potent divalent peptide and contained a single amino acid, deletion in the exosite binding region with respect to the equivalent, region of the natural thrombin inhibitor hirudin. The interaction energies, of the active site, transition state, and exosite binding regions of these, new divalent thrombin inhibitors are not additive.

Disease

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

About this Structure

1DIT is a Protein complex structure of sequences from Homo sapiens with FMT as ligand. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.

Reference

Synthesis, structure, and structure-activity relationships of divalent thrombin inhibitors containing an alpha-keto-amide transition-state mimetic., Krishnan R, Tulinsky A, Vlasuk GP, Pearson D, Vallar P, Bergum P, Brunck TK, Ripka WC, Protein Sci. 1996 Mar;5(3):422-33. PMID:8868478

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