1dwb

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Revision as of 14:30, 12 November 2007

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spinqualitylabelsall models 1dwb, resolution 3.16Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTALLOGRAPHIC ANALYSIS AT 3.0-ANGSTROMS RESOLUTION OF THE BINDING TO HUMAN THROMBIN OF FOUR ACTIVE SITE-DIRECTED INHIBITORS

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The mode of binding of four active-site directed inhibitors to human, thrombin has been determined by x-ray crystallographic analysis. The, inhibitors studied are benzamidine, PPACK, NAPAP, and MD-805, of which the, last three are compounds evolved specifically to inhibit thrombin. Crystal, structures were determined in the presence of both the inhibitor and the, undecapeptide [des-amino Asp55]hirudin(55-65) which binds distant from the, active site. Despite having significantly different chemical structures, NAPAP and MD-805 bind to thrombin in a very similar "inhibitor binding, mode" which is not that expected by direct analogy with the binding of, substrate. Both inhibitors bind to thrombin in a similar way as to, trypsin, but thrombin has an extra loop, the "Tyr-Pro-Pro-Trp loop," not, present in trypsin, which gives further binding interactions and is seen, to move somewhat to accommodate binding of the different inhibitors. The, fact that NAPAP and MD-805 require different stereochemistry for potent, inhibition is demonstrated, and its structural basis clarified. The wealth, of data on analogs and variants of these lead compounds is shown to be, compatible with this inhibitor binding mode.

Disease

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

About this Structure

1DWB is a Protein complex structure of sequences from Hirudo medicinalis and Homo sapiens with BEN as ligand. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.

Reference

Crystallographic analysis at 3.0-A resolution of the binding to human thrombin of four active site-directed inhibitors., Banner DW, Hadvary P, J Biol Chem. 1991 Oct 25;266(30):20085-93. PMID:1939071

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