A Model of Peptide Triazole Entry Inhibitor Binding to HIV-1 gp120 and the Mechanism of Bridging Sheet Disruption
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- 作者：Ali Emileh ; Ferit Tuzer ; Herman Yeh ; Muddegowda Umashankara ; Diogo R. M. Moreira ; Judith M. LaLonde ; Carole A. Bewley ; Cameron F. Abrams ; Irwin M. Chaiken
- 刊名：Biochemistry
- 出版年：2013
- 出版时间：April 2, 2013
- 年：2013
- 卷：52
- 期：13
- 页码：2245-2261
- 全文大小：692K
- 年卷期：v.52,no.13(April 2, 2013)
- ISSN：1520-4995
文摘
Peptide triazole (PT) entry inhibitors prevent HIV-1 infection by blocking the binding of viral gp120 to both the HIV-1 receptor and the coreceptor on target cells. Here, we used all-atom explicit solvent molecular dynamics (MD) to propose a model for the encounter complex of the peptide triazoles with gp120. Saturation transfer difference nuclear magnetic resonance (STD NMR) and single-site mutagenesis experiments were performed to test the simulation results. We found that docking of the peptide to a conserved patch of residues lining the 鈥淔43 pocket鈥?of gp120 in a bridging sheet na茂ve gp120 conformation of the glycoprotein led to a stable complex. This pose prevents formation of the bridging sheet minidomain, which is required for receptor鈥揷oreceptor binding, providing a mechanistic basis for dual-site antagonism of this class of inhibitors. Burial of the peptide triazole at the gp120 inner domain鈥搊uter domain interface significantly contributed to complex stability and rationalizes the significant contribution of hydrophobic triazole groups to peptide potency. Both the simulation model and STD NMR experiments suggest that the I-X-W [where X is (2S,4S)-4-(4-phenyl-1H-1,2,3-triazol-1-yl)pyrrolidine] tripartite hydrophobic motif in the peptide is the major contributor of contacts at the gp120鈥揚T interface. Because the model predicts that the peptide Trp side chain hydrogen bonding with gp120 S375 contributes to the stability of the PT鈥揼p120 complex, we tested this prediction through analysis of peptide binding to gp120 mutant S375A. The results showed that a peptide triazole KR21 inhibits S375A with 20-fold less potency than WT, consistent with predictions of the model. Overall, the PT鈥揼p120 model provides a starting point for both the rational design of higher-affinity peptide triazoles and the development of structure-minimized entry inhibitors that can trap gp120 into an inactive conformation and prevent infection.