8euv

From Proteopedia

Cryo-EM structure of HIV-1 BG505 DS-SOSIP ENV trimer bound to VRC34.01-COMBO1 FAB

Structural highlights

8euv is a 12 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 2.6Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

Q2N0S6_9HIV1 The envelope glyprotein gp160 precursor down-modulates cell surface CD4 antigen by interacting with it in the endoplasmic reticulum and blocking its transport to the cell surface (By similarity).[RuleBase:RU004292][SAAS:SAAS000328_004_020447] The gp120-gp41 heterodimer allows rapid transcytosis of the virus through CD4 negative cells such as simple epithelial monolayers of the intestinal, rectal and endocervical epithelial barriers. Both gp120 and gp41 specifically recognize glycosphingolipids galactosyl-ceramide (GalCer) or 3' sulfo-galactosyl-ceramide (GalS) present in the lipid rafts structures of epithelial cells. Binding to these alternative receptors allows the rapid transcytosis of the virus through the epithelial cells. This transcytotic vesicle-mediated transport of virions from the apical side to the basolateral side of the epithelial cells does not involve infection of the cells themselves (By similarity).[SAAS:SAAS000328_004_240990]

Publication Abstract from PubMed

The HIV-1 fusion peptide (FP) represents a promising vaccine target, but global FP sequence diversity among circulating strains has limited anti-FP antibodies to ~60% neutralization breadth. Here we evolve the FP-targeting antibody VRC34.01 in vitro to enhance FP-neutralization using site saturation mutagenesis and yeast display. Successive rounds of directed evolution by iterative selection of antibodies for binding to resistant HIV-1 strains establish a variant, VRC34.01_mm28, as a best-in-class antibody with 10-fold enhanced potency compared to the template antibody and ~80% breadth on a cross-clade 208-strain neutralization panel. Structural analyses demonstrate that the improved paratope expands the FP binding groove to accommodate diverse FP sequences of different lengths while also recognizing the HIV-1 Env backbone. These data reveal critical antibody features for enhanced neutralization breadth and potency against the FP site of vulnerability and accelerate clinical development of broad HIV-1 FP-targeting vaccines and therapeutics.

Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site.,Banach BB, Pletnev S, Olia AS, Xu K, Zhang B, Rawi R, Bylund T, Doria-Rose NA, Nguyen TD, Fahad AS, Lee M, Lin BC, Liu T, Louder MK, Madan B, McKee K, O'Dell S, Sastry M, Schon A, Bui N, Shen CH, Wolfe JR, Chuang GY, Mascola JR, Kwong PD, DeKosky BJ Nat Commun. 2023 Nov 21;14(1):7593. doi: 10.1038/s41467-023-42098-5. PMID:37989731^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Banach BB, Pletnev S, Olia AS, Xu K, Zhang B, Rawi R, Bylund T, Doria-Rose NA, Nguyen TD, Fahad AS, Lee M, Lin BC, Liu T, Louder MK, Madan B, McKee K, O'Dell S, Sastry M, Schön A, Bui N, Shen CH, Wolfe JR, Chuang GY, Mascola JR, Kwong PD, DeKosky BJ. Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site. Nat Commun. 2023 Nov 21;14(1):7593. PMID:37989731 doi:10.1038/s41467-023-42098-5