The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation
The positive transcription elongation factor b (P‐TEFb) (CDK9/cyclin T (CycT)) promotes mRNA transcriptional elongation through phosphorylation of elongation repressors and RNA polymerase II. To understand the regulation of a transcriptional CDK by its cognate cyclin, we have determined the structur...
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Published in | The EMBO journal Vol. 27; no. 13; pp. 1907 - 1918 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Chichester, UK
John Wiley & Sons, Ltd
09.07.2008
Blackwell Publishing Ltd Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | The positive transcription elongation factor b (P‐TEFb) (CDK9/cyclin T (CycT)) promotes mRNA transcriptional elongation through phosphorylation of elongation repressors and RNA polymerase II. To understand the regulation of a transcriptional CDK by its cognate cyclin, we have determined the structures of the CDK9/CycT1 and free cyclin T2. There are distinct differences between CDK9/CycT1 and the cell cycle CDK CDK2/CycA manifested by a relative rotation of 26° of CycT1 with respect to the CDK, showing for the first time plasticity in CDK cyclin interactions. The CDK9/CycT1 interface is relatively sparse but retains some core CDK–cyclin interactions. The CycT1 C‐terminal helix shows flexibility that may be important for the interaction of this region with HIV TAT and HEXIM. Flavopiridol, an anticancer drug in phase II clinical trials, binds to the ATP site of CDK9 inducing unanticipated structural changes that bury the inhibitor. CDK9 activity and recognition of regulatory proteins are governed by autophosphorylation. We show that CDK9/CycT1 autophosphorylates on Thr186 in the activation segment and three C‐terminal phosphorylation sites. Autophosphorylation on all sites occurs in cis. |
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Bibliography: | ark:/67375/WNG-DFFW19LV-J Supplementary Figure S1Supplementary Figure S2Supplementary Figure S3Supplementary Figure S4Supplementary Figure S5Supplementary Figure S6Supplementary Figure S7Supplementary Data istex:81902F7A11EFE18B01FFB2968CB4EFE7EF108EF7 ArticleID:EMBJ2008121 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work Present address: Istituto di Ricerche di Biologia Molecolare P Angeletti, 00040 Pomezia, Rome, Italy |
ISSN: | 0261-4189 1460-2075 |
DOI: | 10.1038/emboj.2008.121 |