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Crystal structure of human CDK4 in complex with a D-type cyclin

Day, Philip J and Cleasby, Anne and Tickle, Ian J and O'Reilly, Marc and Coyle, Joe E and Holding, Finn P and McMenamin, Rachel L and Yon, Jeff and Chopra, Rajiv and Lengauer, Christoph and Jhoti, Harren (2009) Crystal structure of human CDK4 in complex with a D-type cyclin. Proceedings of the National Academy of Sciences of the United States of America, 106 (11). pp. 4166-4170. ISSN 1091-6490

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.

Item Type: Article
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Additional Information: Author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: cell cycle; kinase; X-ray; CDK4; cyclinD
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Date Deposited: 22 Feb 2010 11:50
Last Modified: 31 Jan 2013 00:50
URI: https://oak.novartis.com/id/eprint/1743

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