The CDK9 C-helix Exhibits Conformational Plasticity That May Explain the Selectivity of CAN508

被引：51

作者：

Baumli, Sonja ^{[1
,2
,3
]}

Hole, Alison J. ^{[1
,2
,3
]}

Noble, Martin E. M. ^{[1
,2
,3
]}

Endicott, Jane A. ^{[1
,2
,3
]}

机构：

[1] Newcastle Univ, No Inst Canc Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[2] Univ Oxford, Dept Biochem, Oxford OX1 3QU, England

[3] Univ Oxford, Lab Mol Biophys, Oxford OX1 3QU, England

来源：

ACS CHEMICAL BIOLOGY | 2012年 / 7卷 / 05期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

P-TEFB; CRYSTAL-STRUCTURE; INHIBITORS; FLAVOPIRIDOL; KINASES; COMPLEX; CANCER; HIV-1;

D O I：

10.1021/cb2004516

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

CDK9 is the kinase of positive transcription elongation factor b and facilitates the transition of paused RNA polymerase II to processive transcription elongation. CDK9 is a validated target for the treatment of cancer, cardiac hypertrophy, and human immunodeficiency virus. Here we analyze different CDK9/cyclin T variants to identify a form of the complex amenable to use in inhibitor design. To demonstrate the utility of this system, we have determined the crystal structures of CDK9/cyclin T and CDK2/cyclin A bound to the CDK9-specific inhibitor CAN508. Comparison of the structures reveals CDK9-specific conformational changes and identifies a CDK9-specific hydrophobic pocket, adjacent to the alpha C-helix. By comparison with a previously published structure of CDK9/cyclin T/human immunodeficiency virus TAT we find that the CDK9 alpha C-helix has a degree of conformational variability that has the potential to be exploited for inhibitor design.

引用

页码：811 / 816

页数：6

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