2b7a

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spinqualitylabelsall models 2b7a, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

The structural basis of Janus Kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

JAK2, a member of the Janus kinase (JAK) family of protein tyrosine, kinases (PTKs), is an important intracellular mediator of cytokine, signaling. Mutations of the JAK2 gene are associated with hematologic, cancers, and aberrant JAK activity is also associated with a number of, immune diseases, including rheumatoid arthritis. Accordingly, the, development of JAK2-specific inhibitors has tremendous clinical relevance., Critical to the function of JAK2 is its PTK domain. We report the 2.0 A, crystal structure of the active conformation of the JAK2 PTK domain in, complex with a high-affinity, pan-JAK inhibitor that appears to bind via, an induced fit mechanism. This inhibitor, the tetracyclic pyridone, 2-tert-butyl-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinoline-7-1, , was buried deep within a constricted ATP-binding site, in which, extensive interactions, including residues that are unique to JAK2 and the, JAK family, are made with the inhibitor. We present a structural basis of, high-affinity JAK-specific inhibition that will undoubtedly provide an, invaluable tool for the further design of novel, potent, and specific, therapeutics against the JAK family.

Disease

Known diseases associated with this structure: Budd-Chiari syndrome OMIM:[147796], Leukemia, acute myelogenous OMIM:[147796], Myelofibrosis, idiopathic OMIM:[147796], Myeloproliferative disorder with erythrocytosis OMIM:[147796], Polycythemia vera OMIM:[147796], Thrombocythemia, essential OMIM:[147796]

About this Structure

2B7A is a Single protein structure of sequence from Homo sapiens with IZA as ligand. Active as Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2 Full crystallographic information is available from OCA.

Reference

The structural basis of Janus kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor., Lucet IS, Fantino E, Styles M, Bamert R, Patel O, Broughton SE, Walter M, Burns CJ, Treutlein H, Wilks AF, Rossjohn J, Blood. 2006 Jan 1;107(1):176-83. Epub 2005 Sep 20. PMID:16174768

Page seeded by OCA on Mon Nov 12 20:59:22 2007