Journal article
A model of the peptide triazole entry inhibitor binding to HIV-1 gp120 and mechanism of bridging sheet disruption
Biochemistry (Easton), v 52(13), pp 2245-2261
02 Apr 2013
PMID: 23470147
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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 “F43 pocket” of gp120 in a bridging sheet naïve gp120 conformation of the glycoprotein led to a stable complex. This pose prevents formation of the bridging sheet minidomain, which is required for receptor–coreceptor binding, providing a mechanistic basis for dual-site antagonism of this class of inhibitors. Burial of the peptide triazole at the gp120 inner domain–outer 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–PT interface. Because the model predicts that the peptide Trp side chain hydrogen bonding with gp120 S375 contributes to the stability of the PT–gp120 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–gp120 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.
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Details
- Title
- A model of the peptide triazole entry inhibitor binding to HIV-1 gp120 and mechanism of bridging sheet disruption
- Creators
- Ali Emileh - Drexel UniversityFerit Tuzer - Drexel UniversityHerman Yeh - National Institute of Diabetes and Digestive and Kidney DiseasesMuddegowda Umashankara - Drexel UniversityDiogo R. M Moreira - Drexel UniversityJudith M LaLonde - Bryn Mawr CollegeCarole A Bewley - National Institute of Diabetes and Digestive and Kidney DiseasesCameron F Abrams - Drexel UniversityIrwin M Chaiken - Drexel University
- Publication Details
- Biochemistry (Easton), v 52(13), pp 2245-2261
- Publisher
- American Chemical Society; Washington, DC
- Number of pages
- 17
- Grant note
- P01 GM056550 || GM / National Institute of General Medical Sciences : NIGMS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; Chemical and Biological Engineering
- Web of Science ID
- WOS:000317172900009
- Scopus ID
- 2-s2.0-84875762591
- Other Identifier
- 991014877806704721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology