3EYH

Crystal structures of JAK1 and JAK2 inhibitor complexes

Summary for 3EYH

• Entry DOI: 10.2210/pdb3eyh/pdb
• Related: 3EYG
• Descriptor: Tyrosine-protein kinase, 2-TERT-BUTYL-9-FLUORO-3,6-DIHYDRO-7H-BENZ[H]-IMIDAZ[4,5-F]ISOQUINOLINE-7-ONE (3 entities in total)
• Functional Keywords: jak kinase, atp-binding, kinase, nucleotide-binding, phosphoprotein, sh2 domain, transferase, tyrosine-protein kinase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 33798.55

Authors

Williams, N.K.,Bamert, R.S.,Patell, O.,Wang, C.,Walden, P.M.,Fantino, E. (deposition date: 2008-10-20, release date: 2009-02-03, Last modification date: 2023-12-27)

Primary citation

Williams, N.K.,Bamert, R.S.,Patel, O.,Wang, C.,Walden, P.M.,Wilks, A.F.,Fantino, E.,Rossjohn, J.,Lucet, I.S.
Dissecting specificity in the Janus kinases: the structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains.
J.Mol.Biol., 387:219-232, 2009

PubMed Abstract: The Janus kinases (JAKs) are a pivotal family of protein tyrosine kinases (PTKs) that play prominent roles in numerous cytokine signaling pathways, with aberrant JAK activity associated with a variety of hematopoietic malignancies, cardiovascular diseases and immune-related disorders. Whereas the structures of the JAK2 and JAK3 PTK domains have been determined, the structure of the JAK1 PTK domain is unknown. Here, we report the high-resolution crystal structures of the "active form" of the JAK1 PTK domain in complex with two JAK inhibitors, a tetracyclic pyridone 2-t-butyl-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinoline-7-one (CMP6) and (3R,4R)-3-[4-methyl-3-[N-methyl-N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropionitrile (CP-690,550), and compare them with the corresponding JAK2 PTK inhibitor complexes. Both inhibitors bound in a similar manner to JAK1, namely buried deep within a constricted ATP-binding site, thereby providing a basis for the potent inhibition of JAK1. As expected, the mode of inhibitor binding in JAK1 was very similar to that observed in JAK2, highlighting the challenges in developing JAK-specific inhibitors that target the ATP-binding site. Nevertheless, differences surrounding the JAK1 and JAK2 ATP-binding sites were apparent, thereby providing a platform for the rational design of JAK2- and JAK1-specific inhibitors.

PubMed: 19361440
DOI: 10.1016/j.jmb.2009.01.041

Experimental method

X-RAY DIFFRACTION (2 Å)