2B7A

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

Summary for 2B7A

• Entry DOI: 10.2210/pdb2b7a/pdb
• Descriptor: Tyrosine-protein kinase JAK2, 2-TERT-BUTYL-9-FLUORO-3,6-DIHYDRO-7H-BENZ[H]-IMIDAZ[4,5-F]ISOQUINOLINE-7-ONE (3 entities in total)
• Functional Keywords: kinase, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Endomembrane system ; Peripheral membrane protein : O60674
• Total number of polymer chains: 2
• Total formula weight: 69803.44

Authors

Lucet, I.S.,Fantino, E.,Styles, M.,Bamert, R.,Patel, O.,Broughton, S.E.,Walter, M.,Burns, C.J.,Treutlein, H.,Wilks, A.F.,Rossjohn, J. (deposition date: 2005-10-04, release date: 2006-01-10, Last modification date: 2024-10-16)

Primary citation

Lucet, I.S.,Fantino, E.,Styles, M.,Bamert, R.,Patel, O.,Broughton, S.E.,Walter, M.,Burns, C.J.,Treutlein, H.,Wilks, A.F.,Rossjohn, J.
The structural basis of Janus kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor.
Blood, 107:176-183, 2006

PubMed Abstract: 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.

PubMed: 16174768
DOI: 10.1182/blood-2005-06-2413

Experimental method

X-RAY DIFFRACTION (2 Å)