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

Philip J. Day, Anne Cleasby, Ian J. Tickle, Marc O'Reilly, Joe E. Coyle, Finn P. Holding, Rachel L. McMenamin, Jeff Yon, Rajiv Chopra, Christoph Lengauer, Harren Jhoti

Research output: Contribution to journalArticlepeer-review

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 Å. 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.

Original languageEnglish (US)
Pages (from-to)4166-4170
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number11
DOIs
StatePublished - Mar 17 2009
Externally publishedYes

Keywords

  • CDK4
  • Cell cycle
  • Cyclind
  • Kinase
  • X-ray

ASJC Scopus subject areas

  • General

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