EMD-20151
C3 symmetry reconstruction of CD4- and 17-bound B41 HIV-1 Env SOSIP in complex with DDM
EMD-20151
Single-particle3.5 Å
![EMD-20151](https://www.ebi.ac.uk/emdb/images/entry/EMD-20151/400_20151.gif)
Map released: 21/10/2020
Last modified: 09/10/2024
Sample Organism:
Human immunodeficiency virus 1,
Homo sapiens
Sample: HIV-1 Env B41 SOSIP in complex with soluble CD4, 17b Fab and DDM
Fitted models: 6opo (Avg. Q-score: 0.448)
Deposition Authors: Ozorowski G, Torres JL
Sample: HIV-1 Env B41 SOSIP in complex with soluble CD4, 17b Fab and DDM
Fitted models: 6opo (Avg. Q-score: 0.448)
Deposition Authors: Ozorowski G, Torres JL
![](http://www.ebi.ac.uk/web_guidelines/images/logos/orcid/orcid_16x16.png)
A Strain-Specific Inhibitor of Receptor-Bound HIV-1 Targets a Pocket near the Fusion Peptide.
Abstract:
Disruption of viral fusion represents a viable, albeit under-explored, target for HIV therapeutics. Here, while studying the receptor-bound envelope glycoprotein conformation by cryoelectron microscopy (cryo-EM), we identify a pocket near the base of the trimer containing a bound detergent molecule and perform in silico drug screening by using a library of drug-like and commercially available molecules. After down-selection, we solve cryo-EM structures that validate the binding of two small molecule hits in very similar manners to the predicted binding poses, including interactions with aromatic residues within the fusion peptide. One of the molecules demonstrates low micromolar inhibition of the autologous virus by using a very rare phenylalanine in the fusion peptide and stabilizing the surrounding region. This work demonstrates that small molecules can target the fusion process, providing an additional target for anti-HIV therapeutics, and highlights the need to explore how fusion peptide sequence variations affect receptor-mediated conformational states across diverse HIV strains.
Disruption of viral fusion represents a viable, albeit under-explored, target for HIV therapeutics. Here, while studying the receptor-bound envelope glycoprotein conformation by cryoelectron microscopy (cryo-EM), we identify a pocket near the base of the trimer containing a bound detergent molecule and perform in silico drug screening by using a library of drug-like and commercially available molecules. After down-selection, we solve cryo-EM structures that validate the binding of two small molecule hits in very similar manners to the predicted binding poses, including interactions with aromatic residues within the fusion peptide. One of the molecules demonstrates low micromolar inhibition of the autologous virus by using a very rare phenylalanine in the fusion peptide and stabilizing the surrounding region. This work demonstrates that small molecules can target the fusion process, providing an additional target for anti-HIV therapeutics, and highlights the need to explore how fusion peptide sequence variations affect receptor-mediated conformational states across diverse HIV strains.