Abstract
The viral encoded Tat protein is essential for the transcriptional activation of HIV proviral DNA. Interaction of Tat with a cellular transcription elongation factor P-TEFb containing CycT1 is critically required for its action. In this study, we performed MD simulation using the 3D data for wild-type and 4CycT1mutants3D data. We found that the dynamic structural change of CycT1 H2’ helix is indispensable for its activity for the Tat action. Moreover, we detected flexible structural changes of the Tat-recognition cavity in the WT CycT1 comprising of ten AAs that are in contact with Tat. These structural fluctuations in WT were lost in the CycT1 mutants. We also found the critical importance of the hydrogen bond network involving H1, H1’ and H2 helices of CycT1. Since similar AA substitutions of the Tat-CycT1 chimera retained the Tat-supporting activity, these interactions are considered primarily involved in interaction with Tat. These findings described in this paper should provide vital information for the development of effective anti-Tat compound.
Highlights
Human immunodeficiency virus type 1 (HIV-1) currently infects an estimated 35.3 million people worldwide, and the numbers of infected people and death due to AIDS continue to rise despise the availability of antiviral drugs [1]
The crystal structure of trimolecular complex consisting of cyclin T1 (CycT1), cyclin-dependent kinase 9 (Cdk9) and Tat has recently been resolved by Tahirov et al [19]
In the 3D structural model of the CycT1-CDK9-Tat complex (3MI9) [19], the Tat Recognition Residues (TRR) is uniquely involved in the CycT1-Tat but not CycT1-CDK9 interaction
Summary
Human immunodeficiency virus type 1 (HIV-1) currently infects an estimated 35.3 million people worldwide, and the numbers of infected people and death due to AIDS continue to rise despise the availability of antiviral drugs [1]. Since current anti-HIV-1 drugs mainly target viral protease and reverse transcriptase, selective drug pressure coupled with the high rate of HIV-1 infection and high mutation rate during each infection cycle quickly confer resistance to these drugs [2]. Development of new anti-HIV-1 therapeutics targeting additional vial and cellular cofactors such as viral transcription that is essential for viral replication remains a pressing need. The Tat-mediated trans-activation of HIV-1 provirus requires an interaction among a cellular transcription factor, positive transcription elongation factor b (P-TEFb), Tat and TAR element, an RNA stem-loop structure formed at PLOS ONE | DOI:10.1371/journal.pone.0119451. The Tat-mediated trans-activation of HIV-1 provirus requires an interaction among a cellular transcription factor, positive transcription elongation factor b (P-TEFb), Tat and TAR element, an RNA stem-loop structure formed at PLOS ONE | DOI:10.1371/journal.pone.0119451 March 17, 2015
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