1qur

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spinqualitylabelsall models 1qur, resolution 2.0Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

HUMAN ALPHA-THROMBIN IN COMPLEX WITH BIVALENT, BENZAMIDINE-BASED SYNTHETIC INHIBITOR

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Two bivalent thrombin inhibitors were synthesized, which consist of a, benzamidine-based active-site-blocking segment, a fibrinogen recognition, exosite inhibitor and a peptidic linker connecting these fragments. BZA-1, hirulog contains an Nalpha-(2-naphthylsulfonyl)-S-3-amidinophenylalanyl-is, onipecotic acid residue connected via the carboxyl group to the linker, segment. The active-site-directed moiety of BZA-2 hirulog, [Nalpha-(2-naphthylsulfonyl-glutamyl)-R-4-amidinophenylal anyl-piperid, ide] was coupled to the linker via the side chain of the glutamic acid., Both BZA-hirulogs contain almost identical linker-exo site inhibitor, parts, except for the substitution of a glycine as the first linker, residue in BZA-1 hirulog by a gamma-amino butyric acid in BZA-2 hirulog, thus increasing flexibility and linker length by two additional atoms., BZA-1 hirulog showed moderate potency (Ki = 0. 50 +/- 0.14 nM), while, BZA-2 hirulog was characterized as a slow, tight binding inhibitor of, thrombin (Ki = 0.29 +/- 0.08 pM). The stability in human plasma of both, analogs was strongly improved compared with hirulog-1. For BZA-2 hirulog a, significantly reduced plasma clearance was observed after intravenous, injection in rats compared with BZA-1 hirulog and hirulog-1. The X-ray, structure of the BZA-2 hirulog in complex with human alpha-thrombin was, solved and confirmed the expected bivalent binding mode.

Disease

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

About this Structure

1QUR is a Single protein structure of sequence from Homo sapiens with NAS, GLU, APH and PIP as ligands. Full crystallographic information is available from OCA.

Reference

Design and evaluation of novel bivalent thrombin inhibitors based on amidinophenylalanines., Steinmetzer T, Renatus M, Kunzel S, Eichinger A, Bode W, Wikstrom P, Hauptmann J, Sturzebecher J, Eur J Biochem. 1999 Oct;265(2):598-605. PMID:10504391

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