title: Crystal structure of human CDK4 in complex with a D-type cyclin.
abstract: The cyclin D1-cyclin-dependent kinase 4 (CDK4) complex is a key regulator of the transition through the G(1) phase of the cell cycle. Among the cyclin/CDKs, CDK4 and cyclin D1 are the most frequently activated by somatic genetic alterations in multiple tumor types. Thus, aberrant regulation of the CDK4/cyclin D1 pathway plays an essential role in oncogenesis; hence, CDK4 is a genetically validated therapeutic target. Although X-ray crystallographic structures have been determined for various CDK/cyclin complexes, CDK4/cyclin D1 has remained highly refractory to structure determination. Here, we report the crystal structure of CDK4 in complex with cyclin D1 at a resolution of 2.3 A. Although CDK4 is bound to cyclin D1 and has a phosphorylated T-loop, CDK4 is in an inactive conformation and the conformation of the heterodimer diverges from the previously known CDK/cyclin binary complexes, which suggests a unique mechanism for the process of CDK4 regulation and activation.
authors.affiliation: Astex Therapeutics Ltd., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Day
authors.forename: Anne
authors.initials: A
authors.lastname: Cleasby
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Tickle
authors.forename: Marc
authors.initials: M
authors.lastname: O'Reilly
authors.forename: Joe E
authors.initials: JE
authors.lastname: Coyle
authors.forename: Finn P
authors.initials: FP
authors.lastname: Holding
authors.forename: Rachel L
authors.initials: RL
authors.lastname: McMenamin
authors.forename: Jeff
authors.initials: J
authors.lastname: Yon
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chopra
authors.forename: Christoph
authors.initials: C
authors.lastname: Lengauer
authors.forename: Harren
authors.initials: H
authors.lastname: Jhoti
mesh_terms: D018360:Crystallography, X-Ray; D019938:Cyclin D1 / Q000737:chemistry*; D051358:Cyclin-Dependent Kinase 4 / Q000737:chemistry*; D006801:Humans; D046912:Multiprotein Complexes / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D046912:Multiprotein Complexes; D019938:Cyclin D1; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4