title: Crystal structures of PRK1 in complex with the clinical compounds lestaurtinib and tofacitinib reveal ligand induced conformational changes.
abstract: Protein kinase C related kinase 1 (PRK1) is a component of Rho-GTPase, androgen receptor, histone demethylase and histone deacetylase signaling pathways implicated in prostate and ovarian cancer. Herein we describe the crystal structure of PRK1 in apo form, and also in complex with a panel of literature inhibitors including the clinical candidates lestaurtinib and tofacitinib, as well as the staurosporine analog Ro-31-8220. PRK1 is a member of the AGC-kinase class, and as such exhibits the characteristic regulatory sequence at the C-terminus of the catalytic domain--the 'C-tail'. The C-tail fully encircles the catalytic domain placing a phenylalanine in the ATP-binding site. Our inhibitor structures include examples of molecules which both interact with, and displace the C-tail from the active site. This information may assist in the design of inhibitors targeting both PRK and other members of the AGC kinase family.
authors.affiliation: Celgene Corporation, San Diego, California, United States of America; Department of Biochemistry and Structural Biology, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Philip
authors.initials: P
authors.lastname: Chamberlain
authors.affiliation: Celgene Corporation, San Diego, California, United States of America.
authors.forename: Silvia
authors.initials: S
authors.lastname: Delker
authors.affiliation: Celgene Corporation, San Diego, California, United States of America.
authors.forename: Barbra
authors.initials: B
authors.lastname: Pagarigan
authors.affiliation: Celgene Corporation, San Diego, California, United States of America.
authors.forename: Afshin
authors.initials: A
authors.lastname: Mahmoudi
authors.affiliation: Celgene Corporation, San Diego, California, United States of America.
authors.forename: Pilgrim
authors.initials: P
authors.lastname: Jackson
authors.affiliation: Celgene Corporation, San Diego, California, United States of America.
authors.forename: Mahan
authors.initials: M
authors.lastname: Abbasian
authors.affiliation: Celgene Corporation, San Diego, California, United States of America.
authors.forename: Jeff
authors.initials: J
authors.lastname: Muir
authors.affiliation: Celgene Corporation, San Diego, California, United States of America.
authors.forename: Neil
authors.initials: N
authors.lastname: Raheja
authors.affiliation: Celgene Corporation, San Diego, California, United States of America.
authors.forename: Brian
authors.initials: B
authors.lastname: Cathers
mesh_terms: D001051:Apoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D002227:Carbazoles / Q000378:metabolism* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D005663:Furans; D006801:Humans; D008024:Ligands; D010880:Piperidines / Q000378:metabolism* / Q000494:pharmacology*; D011487:Protein Conformation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D011743:Pyrimidines / Q000378:metabolism* / Q000494:pharmacology*; D011758:Pyrroles / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D001051:Apoenzymes; D002227:Carbazoles; D005663:Furans; D008024:Ligands; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; C119379:lestaurtinib; C061570:protein kinase N; D011493:Protein Kinase C
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