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Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4166-70. doi: 10.1073/pnas.0809645106. Epub 2009 Feb 23.

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

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  • 1Astex Therapeutics Ltd., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.

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.

PMID:
19237565
[PubMed - indexed for MEDLINE]
PMCID:
PMC2657441
Free PMC Article
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