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

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

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.

MeSH terms

  • Crystallography, X-Ray
  • Cyclin D1 / chemistry*
  • Cyclin-Dependent Kinase 4 / chemistry*
  • Humans
  • Multiprotein Complexes / chemistry
  • Protein Binding
  • Protein Conformation

Substances

  • Multiprotein Complexes
  • Cyclin D1
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4

Associated data

  • PDB/2W96
  • PDB/2W99
  • PDB/2W9F
  • PDB/2W9Z