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2b7a
From Proteopedia
Contents |
The structural basis of Janus Kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor
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.
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
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Disease
Known disease associated with this structure: Leukemia, acute myelogenous OMIM:[147796], Myelofibrosis, idiopathic OMIM:[147796], Myeloproliferative disorder with erythrocytosis OMIM:[147796], Polycythemia vera OMIM:[147796], Thrombocythemia, essential OMIM:[147796], Budd-Chiari syndrome OMIM:[147796]
About this Structure
2B7A is a 2 chains structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
- Lucet IS, Fantino E, Styles M, Bamert R, Patel O, Broughton SE, Walter M, Burns CJ, Treutlein H, Wilks AF, Rossjohn J. The structural basis of Janus kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor. Blood. 2006 Jan 1;107(1):176-83. Epub 2005 Sep 20. PMID:16174768 doi:10.1182/blood-2005-06-2413
Page seeded by OCA on Tue Feb 17 12:52:11 2009
Categories: Homo sapiens | Transferase | Bamert, R. | Broughton, S E. | Burns, C J. | Fantino, E. | Lucet, I S. | Patel, O. | Rossjohn, J. | Styles, M. | Treutlein, H. | Walter, M. | Wilks, A F. | Kinase
