HIV-1 Tat binding to PCAF bromodomain: Structural determinants from computational methods

TY - JOUR

T1 - HIV-1 Tat binding to PCAF bromodomain

T2 - Structural determinants from computational methods

AU - Quy, Vo Cam

AU - Pantano, Sergio

AU - Rossetti, Giulia

AU - Giacca, Mauro

AU - Carloni, Paolo

PY - 2012/8/13

Y1 - 2012/8/13

N2 - 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-1BRU 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 HIVZ2 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.

AB - 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-1BRU 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 HIVZ2 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.

KW - Docking

KW - HIV-1

KW - PCAF BRD

KW - Protein-protein interaction

KW - Tat

UR - http://www.scopus.com/inward/record.url?scp=84901347444&partnerID=8YFLogxK

U2 - 10.3390/biology1020277

DO - 10.3390/biology1020277

M3 - Article

AN - SCOPUS:84901347444

SN - 0733-3188

VL - 1

SP - 277

EP - 296

JO - Biology

JF - Biology

IS - 2

ER -