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 language | English (US) |
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Pages (from-to) | 4166-4170 |
Number of pages | 5 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 106 |
Issue number | 11 |
DOIs | |
State | Published - Mar 17 2009 |
Externally published | Yes |
Keywords
- CDK4
- Cell cycle
- Cyclind
- Kinase
- X-ray
ASJC Scopus subject areas
- General