1zhr

From Proteopedia

---

Revision as of 18:28, 12 November 2007

proteopedia linkproteopedia link

spinqualitylabelsall models 1zhr, resolution 1.73Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with Benzamidine (S434A-T475A-C482S-K437A Mutant)

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Activated factor XI (FXIa) is a key enzyme in the amplification phase of, the blood-coagulation cascade. Thus, a selective FXIa inhibitor may have, lesser bleeding liabilities and provide a safe alternative for, antithrombosis therapy to available drugs on the market. In a previous, report, the crystal structures of the catalytic domain of FXIa, (rhFXI(370-607)) in complex with various ecotin mutants have been, described. However, ecotin forms a matrix-like interaction with, rhFXI(370-607) and is impossible to displace with small-molecule, inhibitors; ecotin crystals are therefore not suitable for iterative, structure-based ligand design. In addition, rhFXI(370-607) did not, crystallize in the presence of small-molecule ligands. In order to obtain, the crystal structure of rhFXI(370-607) with a weak small-molecule ligand, namely benzamidine, several rounds of surface-residue mutation were, implemented to promote crystal formation of rhFXI(370-607). A quadruple, mutant of rhFXI(370-607) (rhFXI(370-607)-S434A,T475A,C482S,K437A) readily, crystallized in the presence of benzamidine. The benzamidine in the, preformed crystals was easily exchanged with other FXIa small-molecule, inhibitors. These crystals have facilitated the structure-based design of, small-molecule FXIa inhibitors.

Disease

Known diseases associated with this structure: Factor XI deficiency, autosomal dominant OMIM:[264900], Factor XI deficiency, autosomal recessive OMIM:[264900]

About this Structure

1ZHR is a Single protein structure of sequence from Homo sapiens with BEN as ligand. Active as Coagulation factor XIa, with EC number 3.4.21.27 Full crystallographic information is available from OCA.

Reference

Mutation of surface residues to promote crystallization of activated factor XI as a complex with benzamidine: an essential step for the iterative structure-based design of factor XI inhibitors., Jin L, Pandey P, Babine RE, Weaver DT, Abdel-Meguid SS, Strickler JE, Acta Crystallogr D Biol Crystallogr. 2005 Oct;61(Pt 10):1418-25. Epub 2005, Sep 28. PMID:16204896

Page seeded by OCA on Mon Nov 12 20:34:41 2007