Crystal structure of HIV-1 Tat complexed with human P-TEFb.
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.
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696, USA. ttahirov@unmc.edu
Tahir H
TH
Tahirov
Nigar D
ND
Babayeva
Katayoun
K
Varzavand
Jeffrey J
JJ
Cooper
Stanley C
SC
Sedore
David H
DH
Price
D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D056906:Cyclin T / Q000737:chemistry / Q000378:metabolism; D042863:Cyclin-Dependent Kinase 9 / Q000737:chemistry / Q000378:metabolism; D004789:Enzyme Activation; D015497:HIV-1 / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D042925:Positive Transcriptional Elongation Factor B / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
C503684:CCNT1 protein, human; D056906:Cyclin T; D054322:tat Gene Products, Human Immunodeficiency Virus; D000255:Adenosine Triphosphate; D042925:Positive Transcriptional Elongation Factor B; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9