1a3e

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spinqualitylabelsall models 1a3e, resolution 1.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

COMPLEX OF HUMAN ALPHA-THROMBIN WITH THE BIFUNCTIONAL BORONATE INHIBITOR BOROLOG2

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The crystal structure of the complexes of hirutonin-2 and hirutonin-6 with, human alpha-thrombin have been solved and refined to R-factors of 0.169, (2.0 A resolution) and 0.162 (2.1 A), respectively. Hirutonins belong to a, family of bifunctional inhibitors bearing a noncleavable moiety mimicking, the scissile bond. Hirutonin-2 is an analog of, (D)Phe-Pro-Arg-Gly-hirudin49-65; hirutonin-6 has the same N-terminal, tripeptide connected to a shortened fibrinogen exosite-binding part by a, short, nonpeptidyl linker. The hirutonin-6 molecule is well defined in the, electron density with the exception of the C-terminal Leu-h61. The linker, follows near the bottom of the canyon connecting the active site with the, exosite, forms a short antiparallel beta-sheet-like arrangement with, Leu40-Leu41 and makes van der Waals contacts with Glu39-Leu40-Leu41 of, thrombin. In the thrombin-hirutonin-2 complex, the N- and C-terminal parts, of the inhibitor are well ordered (except the C-terminal Gln-h65) while, the central portion of the linker is partially disordered. The glycine, analog in the P1' position of hirutonin-2 assumes a conformation similar, to that of the canonical form (Bode and Huber (1992) Eur. J. Biochem., 204:433-451) and supports the identification of the S1' site as restricted, by His57, Trp60D, Lys60F, and the Cys42-Cys58 disulfide bridge. The, carbonyl oxygen of the P1 arginine residue is located in the oxyanion hole, formed by the NH groups of Gly193 and Ser195, while the carbonyl carbon is, positioned within a short distance, 2.8 A, from the O gamma of Ser195., This resembles the conformation of the substrate-like inhibitors bound to, other serine proteases. The N-terminal (D)Phe-Pro-Arg fragment common to, both inhibitors binds to thrombin in a fashion very similar to that of, other inhibitors having this motif. The binding of the C-terminus of, hirutonins to the fibrinogen-binding exosite is similar to that observed, in hirudin and hirulog complexes.

Disease

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

About this Structure

1A3E is a Protein complex structure of sequences from Hirudo medicinalis and Homo sapiens with T16 as ligand. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.

Reference

Crystal structure of the complex of human alpha-thrombin and nonhydrolyzable bifunctional inhibitors, hirutonin-2 and hirutonin-6., Zdanov A, Wu S, DiMaio J, Konishi Y, Li Y, Wu X, Edwards BF, Martin PD, Cygler M, Proteins. 1993 Nov;17(3):252-65. PMID:8272424

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