2b7a: Difference between revisions
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'''The structural basis of Janus Kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor'''<br /> | '''The structural basis of Janus Kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor'''<br /> | ||
==Overview== | ==Overview== | ||
JAK2, a member of the Janus kinase (JAK) family of protein tyrosine | 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== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
2B7A is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with IZA as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] Full crystallographic information is available from [http:// | 2B7A is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=IZA:'>IZA</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2B7A OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Transferase]] | [[Category: Transferase]] | ||
[[Category: Bamert, R.]] | [[Category: Bamert, R.]] | ||
[[Category: Broughton, S | [[Category: Broughton, S E.]] | ||
[[Category: Burns, C | [[Category: Burns, C J.]] | ||
[[Category: Fantino, E.]] | [[Category: Fantino, E.]] | ||
[[Category: Lucet, I | [[Category: Lucet, I S.]] | ||
[[Category: Patel, O.]] | [[Category: Patel, O.]] | ||
[[Category: Rossjohn, J.]] | [[Category: Rossjohn, J.]] | ||
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[[Category: Treutlein, H.]] | [[Category: Treutlein, H.]] | ||
[[Category: Walter, M.]] | [[Category: Walter, M.]] | ||
[[Category: Wilks, A | [[Category: Wilks, A F.]] | ||
[[Category: IZA]] | [[Category: IZA]] | ||
[[Category: kinase]] | [[Category: kinase]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:34:52 2008'' | ||
Revision as of 17:34, 21 February 2008
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The structural basis of Janus Kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor
OverviewOverview
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.
DiseaseDisease
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 StructureAbout this Structure
2B7A is a Single protein structure of sequence from Homo sapiens with 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.
ReferenceReference
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
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