5gds

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spinqualitylabelsall models 5gds, resolution 2.1Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

HIRUNORMS ARE TRUE HIRUDIN MIMETICS. THE CRYSTAL STRUCTURE OF HUMAN ALPHA-THROMBIN:HIRUNORM V COMPLEX

Overview

A novel class of synthetic, multisite-directed thrombin inhibitors, known, as hirunorms, has been described recently. These compounds were designed, to mimic the binding mode of hirudin, and they have been proven to be very, strong and selective thrombin inhibitors. Here we report the crystal, structure of the complex formed by human alpha-thrombin and hirunorm V, a, 26-residue polypeptide containing non-natural amino acids, determined at, 2.1 A resolution and refined to an R-factor of 0.176. The structure, reveals that the inhibitor binding mode is distinctive of a true hirudin, mimetic, and it highlights the molecular basis of the high inhibitory, potency (Ki is in the picomolar range) and the strong selectivity of, hirunorm V. Hirunorm V interacts through the N-terminal tetrapeptide with, the thrombin active site in a nonsubstrate mode; at the same time, this, inhibitor specifically binds through the C-terminal segment to the, fibrinogen recognition exosite. The backbone of the N-terminal, tetrapeptide Chg1"-Val2"-2-Nal3"-Thr4" (Chg, cyclohexyl-glycine; 2-Nal, beta-(2-naphthyl)-alanine) forms a short beta-strand parallel to thrombin, main-chain residues Ser214-Gly219. The Chg1" side chain fills the S2, subsite, Val2" is located at the entrance of S1, whereas 2-Nal3" side, chain occupies the aryl-binding site. Such backbone orientation is very, close to that observed for the N-terminal residues of hirudin, and it is, similar to that of the synthetic retro-binding peptide BMS-183507, but it, is opposite to the proposed binding mode of fibrinogen and of small, synthetic substrates. Hirunorm V C-terminal segment binds to the, fibrinogen recognition exosite, similarly to what observed for hirudin, C-termninal tail and related compounds. The linker polypeptide segment, connecting hirunorm V N-and C-terminal regions is not observable in the, electron density maps. The crystallographic analysis proves the, correctness of the design and it provides a compelling proof on the, interaction mechanism for this novel class of high potency, multisite-directed synthetic thrombin inhibitors.

About this Structure

5GDS is a Single protein structure of sequence from Homo sapiens with NAG as ligand. Active as Thrombin, with EC number 3.4.21.5 Structure known Active Site: CAT. Full crystallographic information is available from OCA.

Reference

Hirunorms are true hirudin mimetics. The crystal structure of human alpha-thrombin-hirunorm V complex., De Simone G, Lombardi A, Galdiero S, Nastri F, Della Morte R, Staiano N, Pedone C, Bolognesi M, Pavone V, Protein Sci. 1998 Feb;7(2):243-53. PMID:9521099

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