8czz

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

spinqualitylabelsall models 8czz, resolution 3.14Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8czz is a 18 chain structure with sequence from Homo sapiens and Human immunodeficiency virus 1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.14Å Ligands: 83J, BMA, MAN, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. Structure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir.,Prevost J, Chen Y, Zhou F, Tolbert WD, Gasser R, Medjahed H, Nayrac M, Nguyen DN, Gottumukkala S, Hessell AJ, Rao VB, Pozharski E, Huang RK, Matthies D, Finzi A, Pazgier M Nat Commun. 2023 Oct 23;14(1):6710. doi: 10.1038/s41467-023-42500-2. PMID:37872202 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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