HIV-1 Tat Binding to PCAF Bromodomain: Structural Determinants from Computational Methods

Biology

Vo Cam Quy³  Sergio Pantano²  Giulia Rossetti³  Mauro Giacca¹ 

[1] International Centre for Genetic Engineering and Biotechnology, Trieste 34149, Italy;Institut Pasteur de Montevideo, Mataojo 2020, Montevideo CP 11400, Uruguay;Computational Biophysics, German Research School for Simulation Sciences, Computational Biomedicine, Institute for Advanced Simulation (IAS-5), Forschungszentrum Jülich, Jülich D-52425, Germany;

关键词: Tat;    PCAF BRD;    HIV-1;    docking;    protein-protein interaction;   

DOI  :  10.3390/biology1020277

来源: mdpi

【 摘 要 】

The binding between the HIV-1 trans-activator of transcription (Tat) and p300/(CREB-binding protein)-associated factor (PCAF) bromodomain is a crucial step in the HIV-1 life cycle. However, the structure of the full length acetylated Tat bound to PCAF has not been yet determined experimentally. Acetylation of Tat residues can play a critical role in enhancing HIV-1 transcriptional activation. Here, we have combined a fully flexible protein-protein docking approach with molecular dynamics simulations to predict the structural determinants of the complex for the common HIV-1_BRU variant. This model reproduces all the crucial contacts between the Tat peptide ⁴⁶SYGR(AcK)KRRQRC⁵⁶ and the PCAF bromodomain previously reported by NMR spectroscopy. Additionally, inclusion of the entire Tat protein results in additional contact points at the protein-protein interface. The model is consistent with the available experimental data reported and adds novel information to our previous structural predictions of the PCAF bromodomain in complex with the rare HIV_Z2 variant, which was obtained with a less accurate computational method. This improved characterization of Tat.PCAF bromodomain binding may help in defining the structural determinants of other protein interactions involving lysine acetylation.

【 授权许可】

CC BY   
© 2012 by the authors; licensee MDPI, Basel, Switzerland.