MD simulation of the Tat/Cyclin T1/CDK9 complex revealing the hidden catalytic cavity within the CDK9 molecule upon Tat binding.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Molecular Dynamics Simulation*; Cyclin T/*chemistry ; Cyclin-Dependent Kinase 9/*chemistry ; Multiprotein Complexes/*chemistry ; tat Gene Products, Human Immunodeficiency Virus/*chemistry; Binding Sites ; Catalysis ; Cyclin T/metabolism ; Cyclin-Dependent Kinase 9/metabolism ; Multiprotein Complexes/metabolism ; Protein Binding ; Protein Conformation ; Protein Stability ; Structure-Activity Relationship ; tat Gene Products, Human Immunodeficiency Virus/metabolism

In this study, we applied molecular dynamics (MD) simulation to analyze the dynamic behavior of the Tat/CycT1/CDK9 tri-molecular complex and revealed the structural changes of P-TEFb upon Tat binding. We found that Tat could deliberately change the local flexibility of CycT1. Although the structural coordinates of the H1 and H2 helices did not substantially change, H1', H2', and H3' exhibited significant changes en masse. Consequently, the CycT1 residues involved in Tat binding, namely Tat-recognition residues (TRRs), lost their flexibility with the addition of Tat to P-TEFb. In addition, we clarified the structural variation of CDK9 in complex with CycT1 in the presence or absence of Tat. Interestingly, Tat addition significantly reduced the structural variability of the T-loop, thus consolidating the structural integrity of P-TEFb. Finally, we deciphered the formation of the hidden catalytic cavity of CDK9 upon Tat binding. MD simulation revealed that the PITALRE signature sequence of CDK9 flips the inactive kinase cavity of CDK9 into the active form by connecting with Thr186, which is crucial for its activity, thus presumably recruiting the substrate peptide such as the C-terminal domain of RNA pol II. These findings provide vital information for the development of effective novel anti-HIV drugs with CDK9 catalytic activity as the target.
Competing Interests: The authors have declared that no competing interests exist.

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0 (Cyclin T)
0 (Multiprotein Complexes)
0 (tat Gene Products, Human Immunodeficiency Virus)
EC 2.7.11.22 (Cyclin-Dependent Kinase 9)

Date Created: 20170209 Date Completed: 20170817 Latest Revision: 20181113

20250114

PMC5298246

10.1371/journal.pone.0171727

28178316