1zom

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spinqualitylabelsall models 1zom, resolution 2.25Å 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 a peptidomimetic Inhibitor

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Human coagulation factor XIa (FXIa), a serine protease activated by, site-specific cleavage of factor XI by thrombin, FXIIa, or autoactivation, is a critical enzyme in the amplification phase of the coagulation, cascade. To investigate the potential of FXIa inhibitors as safe, anticoagulants, a series of potent, selective peptidomimetic inhibitors of, FXIa were designed and synthesized. Some of these inhibitors showed low, nanomolar FXIa inhibitory activity with >1000-fold FXa selectivity and, >100-fold thrombin selectivity. The X-ray structure of one of these, inhibitors, 36, demonstrates its unique binding interactions with FXIa., Compound 32 caused a doubling of the activated partial thromboplastin time, in human plasma at 2.4 microM and was efficacious in a rat model of venous, thrombosis. These data suggest that factor XIa plays a significant role in, venous thrombosis and may be a suitable target for the development of, antithrombotic therapy.

Disease

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

About this Structure

1ZOM is a Single protein structure of sequence from Homo sapiens with SO4 and 339 as ligands. Active as Coagulation factor XIa, with EC number 3.4.21.27 Full crystallographic information is available from OCA.

Reference

Design, synthesis, and biological evaluation of peptidomimetic inhibitors of factor XIa as novel anticoagulants., Lin J, Deng H, Jin L, Pandey P, Quinn J, Cantin S, Rynkiewicz MJ, Gorga JC, Bibbins F, Celatka CA, Nagafuji P, Bannister TD, Meyers HV, Babine RE, Hayward NJ, Weaver D, Benjamin H, Stassen F, Abdel-Meguid SS, Strickler JE, J Med Chem. 2006 Dec 28;49(26):7781-91. PMID:17181160

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