1tmu

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spinqualitylabelsall models 1tmu, resolution 2.5Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CHANGES IN INTERACTIONS IN COMPLEXES OF HIRUDIN DERIVATIVES AND HUMAN ALPHA-THROMBIN DUE TO DIFFERENT CRYSTAL FORMS

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The three-dimensional structures of D-Phe-Pro-Arg-chloromethyl, ketone-inhibited thrombin in complex with Tyr-63-sulfated hirudin (ternary, complex) and of thrombin in complex with the bifunctional inhibitor, D-Phe-Pro-Arg-Pro-(Gly)4-hirudin (CGP 50,856, binary complex) have been, determined by X-ray crystallography in crystal forms different from those, described by Skrzypczak-Jankun et al. (Skrzypczak-Jankun, E., Carperos, V.E., Ravichandran, K.G., & Tulinsky, A., 1991, J. Mol. Biol. 221, 1379-1393). In both complexes, the interactions of the C-terminal hirudin, segments of the inhibitors binding to the fibrinogen-binding exosite of, thrombin are clearly established, including residues 60-64, which are, disordered in the earlier crystal form. The interactions of the sulfate, group of Tyr-63 in the ternary complex structure explain why natural, sulfated hirudin binds with a 10-fold lower K(i) than the desulfated, recombinant material. In this new crystal form, the autolysis loop of, thrombin (residues 146-150), which is disordered in the earlier crystal, form, is ordered due to crystal contacts. Interactions between the, C-terminal fragment of hirudin and thrombin are not influenced by crystal, contacts in this new crystal form, in contrast to the earlier form. In the, bifunctional inhibitor-thrombin complex, the peptide bond between Arg-Pro, (P1-P1') seems to be cleaved.

Disease

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

About this Structure

1TMU is a Single protein structure of sequence from Homo sapiens with NAG, SO3 and CH2 as ligands. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.

Reference

Changes in interactions in complexes of hirudin derivatives and human alpha-thrombin due to different crystal forms., Priestle JP, Rahuel J, Rink H, Tones M, Grutter MG, Protein Sci. 1993 Oct;2(10):1630-42. PMID:8251938

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