title: The structural basis of Janus kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor.
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.
authors.affiliation: Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Isabelle S
authors.initials: IS
authors.lastname: Lucet
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Fantino
authors.forename: Michelle
authors.initials: M
authors.lastname: Styles
authors.forename: Rebecca
authors.initials: R
authors.lastname: Bamert
authors.forename: Onisha
authors.initials: O
authors.lastname: Patel
authors.forename: Sophie E
authors.initials: SE
authors.lastname: Broughton
authors.forename: Mark
authors.initials: M
authors.lastname: Walter
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Burns
authors.forename: Herbert
authors.initials: H
authors.lastname: Treutlein
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Wilks
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
mesh_terms: D000255:Adenosine Triphosphate; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D053614:Janus Kinase 2; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2