HIV-1 Tat Binding to PCAF Bromodomain: Structural Determinants from Computational Methods
Abstract
:1. Introduction
2. Results and Discussion
2.1. Intermolecular Contacts
Effect on Tat.PCAF binding | Mutants | In contact with | BRU Tat.PCAF model (docking) | BRU Tat.PCAF model (MD) | Coverage (%) |
---|---|---|---|---|---|
inhibiting binding [18] | AcK50A | F748, V752, Y760, I764 | F748, V752, Y760, I764 | F748, V752, Y760 | 100% |
Y802 | Y802 | Y802 | 80% | ||
Y809 | Y809 | Absent | |||
| | 100% | |||
inhibiting binding [18] | Y47A | V763 | Absent | Absent | |
V763 | Y47 | P804, S807 | N803 | 80% | |
E808 | E808 | 100% | |||
Y809 | 80% | ||||
Q54A | E756 | E756 | E756 | 80% | |
E756A | Q54 | | | 80% | |
strongly diminishing binding [18] | R53E | E756 | | | 100% |
F748A | Tat46SYGR(AcK)KRRQRC56 | AcK50 | AcK50 | 100% | |
V752A | Tat46SYGR(AcK)KRRQRC56 | AcK50, R51 | AcK50, R51 | 100% | |
Y802A | Tat46SYGR(AcK)KRRQRC56 | AcK50 | AcK50 | 100% | |
Y809A | Tat46SYGR(AcK)KRRQRC56 | AcK50, S46 | S46 | 100% | |
Diminishing binding [18] | R49A | PCAF BRD | P747, E750 | W746, P747, E750, Y802 | 100% |
F748 | 80% | ||||
K51A | PCAF BRD | E750, V752, K753 | F748, E750, V752, E756 | 100% | |
K753 | 50% | ||||
R52A | PCAF BRD | K753 | K753 | 25% | |
E756 | E756 | 100% | |||
Diminishing binding [52] | Y760D | AcK50 | AcK50 | AcK50 | 100% |
Y761D | AcK50 | AcK50 | Absent | ||
no effect [18] | W746A, D769A, C799A, N803A | R49 | 100% | ||
E750A | R49 | R49 | 100% | ||
T755A | R53 | R53 | 100% | ||
I764A | AcK50 | AcK50 | 100% | ||
N798A | AcK50 | AcK50 | 100% |
Donors | Acceptors |
---|---|
AcK50 | V752 |
AcK50 | F748 |
AcK50 | Y809 |
AcK50 | Y802 |
N798 | AcK50 |
R49 * | P747* |
R49 * | E750* |
R53 | E756 |
R53 | K753 |
R55 | E756 |
Q54 | E756 |
E2 * | P758* |
P3 * | P758* |
2.2. Structural Rearrangements of Tat and PCAF upon Binding
Systems | Backbone RMSD (Å):PCAF 722–781 | Backbone RMSD (Å): Tat47YGR(AcK)KRRQR55 | Backbone RMSD (Å): Full complex (same residues) | ||||||
---|---|---|---|---|---|---|---|---|---|
min. | max. | avg. | min. | max. | avg. | min. | max. | avg. | |
Tat47YGR(AcK)KRRQR55.PCAF*(1JM4) | 0.6 | 1.5 | 1.0 | 0.7 | 1.2 | 2.3 | 0.9 | 1.9 | 1.33 |
sd. 0.2 | sd. 0.5 | sd. 0.26 | |||||||
Tat47YGR(AcK)KRRQR55.PCAF (Prediction) | 1.3 | 0.9 | 1.7 | ||||||
BRU Tat.PCAF (Prediction by docking) | 0.8 | 4.0 | 14.4 | ||||||
BRU Tat.PCAF (Prediction by MD simulation, the last frame) | 2.9 3.3 3.1 sd. 0.2 | 2.8 3.4 2.6 sd. 0.4 | 24.7 25.8 24.5 sd. 1.2 |
2.3. Key Residues of PCAF BRD for Its Interaction with Tat
Residues | Identity (%) | Residues | Identity (%) |
---|---|---|---|
P747 | 53% | T772 | 69% |
F748 | 91% | Y782 | 97% |
P751 | 68% | F788 | 63% |
V752 | 71% | D791 | 89% |
P758 | 71% | F796 | 60% |
I764 | 76% | N798 | 96% |
P767 | 97% | Y802 | 77% |
D769 | 85% | N803 | 88% |
L770 | 66% |
3. Computational Methods Section
4. Conclusions
Supplementary Files
Acknowledgments
References
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Quy, V.C.; Pantano, S.; Rossetti, G.; Giacca, M.; Carloni, P. HIV-1 Tat Binding to PCAF Bromodomain: Structural Determinants from Computational Methods. Biology 2012, 1, 277-296. https://doi.org/10.3390/biology1020277
Quy VC, Pantano S, Rossetti G, Giacca M, Carloni P. HIV-1 Tat Binding to PCAF Bromodomain: Structural Determinants from Computational Methods. Biology. 2012; 1(2):277-296. https://doi.org/10.3390/biology1020277
Chicago/Turabian StyleQuy, Vo Cam, Sergio Pantano, Giulia Rossetti, Mauro Giacca, and Paolo Carloni. 2012. "HIV-1 Tat Binding to PCAF Bromodomain: Structural Determinants from Computational Methods" Biology 1, no. 2: 277-296. https://doi.org/10.3390/biology1020277