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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2008
|
| _version_ | 1797072632279990272 |
|---|---|
| author | Baumli, S Lolli, G Lowe, E Troiani, S Rusconi, L Bullock, A Debreczeni, J Knapp, S Johnson, L |
| author_facet | Baumli, S Lolli, G Lowe, E Troiani, S Rusconi, L Bullock, A Debreczeni, J Knapp, S Johnson, L |
| author_sort | Baumli, S |
| collection | OXFORD |
| description | 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 degrees 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. |
| first_indexed | 2024-03-06T23:10:34Z |
| format | Journal article |
| id | oxford-uuid:65500a35-bff3-4199-8956-d8665eba43f9 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:10:34Z |
| publishDate | 2008 |
| record_format | dspace |
| spelling | oxford-uuid:65500a35-bff3-4199-8956-d8665eba43f92022-03-26T18:24:46ZThe structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:65500a35-bff3-4199-8956-d8665eba43f9EnglishSymplectic Elements at Oxford2008Baumli, SLolli, GLowe, ETroiani, SRusconi, LBullock, ADebreczeni, JKnapp, SJohnson, LThe 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 degrees 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. |
| spellingShingle | Baumli, S Lolli, G Lowe, E Troiani, S Rusconi, L Bullock, A Debreczeni, J Knapp, S Johnson, L The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation. |
| title | The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation. |
| title_full | The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation. |
| title_fullStr | The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation. |
| title_full_unstemmed | The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation. |
| title_short | The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation. |
| title_sort | structure of p tefb cdk9 cyclin t1 its complex with flavopiridol and regulation by phosphorylation |
| work_keys_str_mv | AT baumlis thestructureofptefbcdk9cyclint1itscomplexwithflavopiridolandregulationbyphosphorylation AT lollig thestructureofptefbcdk9cyclint1itscomplexwithflavopiridolandregulationbyphosphorylation AT lowee thestructureofptefbcdk9cyclint1itscomplexwithflavopiridolandregulationbyphosphorylation AT troianis thestructureofptefbcdk9cyclint1itscomplexwithflavopiridolandregulationbyphosphorylation AT rusconil thestructureofptefbcdk9cyclint1itscomplexwithflavopiridolandregulationbyphosphorylation AT bullocka thestructureofptefbcdk9cyclint1itscomplexwithflavopiridolandregulationbyphosphorylation AT debreczenij thestructureofptefbcdk9cyclint1itscomplexwithflavopiridolandregulationbyphosphorylation AT knapps thestructureofptefbcdk9cyclint1itscomplexwithflavopiridolandregulationbyphosphorylation AT johnsonl thestructureofptefbcdk9cyclint1itscomplexwithflavopiridolandregulationbyphosphorylation AT baumlis structureofptefbcdk9cyclint1itscomplexwithflavopiridolandregulationbyphosphorylation AT lollig structureofptefbcdk9cyclint1itscomplexwithflavopiridolandregulationbyphosphorylation AT lowee structureofptefbcdk9cyclint1itscomplexwithflavopiridolandregulationbyphosphorylation AT troianis structureofptefbcdk9cyclint1itscomplexwithflavopiridolandregulationbyphosphorylation AT rusconil structureofptefbcdk9cyclint1itscomplexwithflavopiridolandregulationbyphosphorylation AT bullocka structureofptefbcdk9cyclint1itscomplexwithflavopiridolandregulationbyphosphorylation AT debreczenij structureofptefbcdk9cyclint1itscomplexwithflavopiridolandregulationbyphosphorylation AT knapps structureofptefbcdk9cyclint1itscomplexwithflavopiridolandregulationbyphosphorylation AT johnsonl structureofptefbcdk9cyclint1itscomplexwithflavopiridolandregulationbyphosphorylation |