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Crystal structure of HIV-1 Tat complexed with human P-TEFb

Author

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  • Tahir H. Tahirov

    (Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696, USA)

  • Nigar D. Babayeva

    (Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696, USA)

  • Katayoun Varzavand

    (University of Iowa, Iowa City, Iowa 52242, USA)

  • Jeffrey J. Cooper

    (University of Iowa, Iowa City, Iowa 52242, USA)

  • Stanley C. Sedore

    (University of Iowa, Iowa City, Iowa 52242, USA)

  • David H. Price

    (University of Iowa, Iowa City, Iowa 52242, USA)

Abstract

Regulation of the expression of the human immunodeficiency virus (HIV) genome is accomplished in large part by controlling transcription elongation. The viral protein Tat hijacks the host cell’s RNA polymerase II elongation control machinery through interaction with the positive transcription elongation factor, P-TEFb, and directs the factor to promote productive elongation of HIV mRNA. Here we describe the crystal structure of the Tat·P-TEFb complex containing HIV-1 Tat, human Cdk9 (also known as CDK9), and human cyclin T1 (also known as CCNT1). Tat adopts a structure complementary to the surface of P-TEFb and makes extensive contacts, mainly with the cyclin T1 subunit of P-TEFb, but also with the T-loop of the Cdk9 subunit. The structure provides a plausible explanation for the tolerance of Tat to sequence variations at certain sites. Importantly, Tat induces significant conformational changes in P-TEFb. This finding lays a foundation for the design of compounds that would specifically inhibit the Tat·P-TEFb complex and block HIV replication.

Suggested Citation

  • Tahir H. Tahirov & Nigar D. Babayeva & Katayoun Varzavand & Jeffrey J. Cooper & Stanley C. Sedore & David H. Price, 2010. "Crystal structure of HIV-1 Tat complexed with human P-TEFb," Nature, Nature, vol. 465(7299), pages 747-751, June.
    • Handle: RePEc:nat:nature:v:465:y:2010:i:7299:d:10.1038_nature09131
    DOI: 10.1038/nature09131
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    Cited by:

    1. Kaori Asamitsu & Takatsugu Hirokawa & Yurina Hibi & Takashi Okamoto, 2015. "Molecular Dynamics Simulation and Experimental Verification of the Interaction between Cyclin T1 and HIV-1 Tat Proteins," PLOS ONE, Public Library of Science, vol. 10(3), pages 1-17, March.
    2. Kaori Asamitsu & Takatsugu Hirokawa & Takashi Okamoto, 2017. "MD simulation of the Tat/Cyclin T1/CDK9 complex revealing the hidden catalytic cavity within the CDK9 molecule upon Tat binding," PLOS ONE, Public Library of Science, vol. 12(2), pages 1-14, February.

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