8CZZ

Cryo-EM structure of T/F100 SOSIP.664 HIV-1 Env trimer with LMHS mutations in complex with Temsavir, 8ANC195, and 10-1074

Summary for 8CZZ

• Entry DOI: 10.2210/pdb8czz/pdb
• EMDB information: 27103
• Descriptor: CRF01_AE T/F100 HIV-1 gp120, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (15 entities in total)
• Functional Keywords: t/f100 sosip, clade a/e hiv-1, 8anc195, 10-1074, bms-626529, temsavir, lmhs mutant., viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 18
• Total formula weight: 537669.84

Authors

Chen, Y.,Pozharski, E.,Tolbert, W.,Pazgier, M. (deposition date: 2022-05-25, release date: 2023-05-31, Last modification date: 2024-10-16)

Primary citation

Prevost, J.,Chen, Y.,Zhou, F.,Tolbert, W.D.,Gasser, R.,Medjahed, H.,Nayrac, M.,Nguyen, D.N.,Gottumukkala, S.,Hessell, A.J.,Rao, V.B.,Pozharski, E.,Huang, R.K.,Matthies, D.,Finzi, A.,Pazgier, M.
Structure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir.
Nat Commun, 14:6710-6710, 2023

PubMed Abstract: The HIV-1 entry inhibitor temsavir prevents the viral receptor CD4 (cluster of differentiation 4) from interacting with the envelope glycoprotein (Env) and blocks its conformational changes. To do this, temsavir relies on the presence of a residue with small side chain at position 375 in Env and is unable to neutralize viral strains like CRF01_AE carrying His375. Here we investigate the mechanism of temsavir resistance and show that residue 375 is not the sole determinant of resistance. At least six additional residues within the gp120 inner domain layers, including five distant from the drug-binding pocket, contribute to resistance. A detailed structure-function analysis using engineered viruses and soluble trimer variants reveals that the molecular basis of resistance is mediated by crosstalk between His375 and the inner domain layers. Furthermore, our data confirm that temsavir can adjust its binding mode to accommodate changes in Env conformation, a property that likely contributes to its broad antiviral activity.

PubMed: 37872202
DOI: 10.1038/s41467-023-42500-2

Experimental method

ELECTRON MICROSCOPY (3.14 Å)