6OPN

CD4- and 17-bound HIV-1 Env B41 SOSIP in complex with small molecule GO35

Summary for 6OPN

• Entry DOI: 10.2210/pdb6opn/pdb
• EMDB information: 20150
• Descriptor: Envelope glycoprotein gp160, Envelope glycoprotein gp41, T-cell surface glycoprotein CD4, ... (7 entities in total)
• Functional Keywords: hiv-1, env, cd4, receptor-bound state, small molecule, fusion inhibitor, viral protein, viral protein-immune system complex, viral protein/immune system
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 9
• Total formula weight: 308830.21

Authors

Ozorowski, G.,Torres, J.L.,Ward, A.B. (deposition date: 2019-04-25, release date: 2020-10-21, Last modification date: 2020-12-09)

Primary citation

Ozorowski, G.,Torres, J.L.,Santos-Martins, D.,Forli, S.,Ward, A.B.
A Strain-Specific Inhibitor of Receptor-Bound HIV-1 Targets a Pocket near the Fusion Peptide.
Cell Rep, 33:108428-108428, 2020

PubMed 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.

PubMed: 33238117
DOI: 10.1016/j.celrep.2020.108428

Experimental method

ELECTRON MICROSCOPY (3.5 Å)