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Structural characterization of a highly-potent V3-glycan broadly neutralizing antibody bound to natively-glycosylated HIV-1 envelope.

Structural characterization of a highly-potent V3-glycan broadly neutralizing antibody bound to natively-glycosylated HIV-1 envelope.
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Barnes CO, Gristick HB, Freund NT, Escolano A, Lyubimov AY, Hartweger H, West AP, Cohen AE, Nussenzweig MC, Bjorkman PJ,


Barnes CO, Gristick HB, Freund NT, Escolano A, Lyubimov AY, Hartweger H, West AP, Cohen AE, Nussenzweig MC, Bjorkman PJ, (click to view)

Barnes CO, Gristick HB, Freund NT, Escolano A, Lyubimov AY, Hartweger H, West AP, Cohen AE, Nussenzweig MC, Bjorkman PJ,

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Nature communications 2018 03 289(1) 1251 doi 10.1038/s41467-018-03632-y

Abstract

Broadly neutralizing antibodies (bNAbs) isolated from HIV-1-infected individuals inform HIV-1 vaccine design efforts. Developing bNAbs with increased efficacy requires understanding how antibodies interact with the native oligomannose and complex-type N-glycan shield that hides most protein epitopes on HIV-1 envelope (Env). Here we present crystal structures, including a 3.8-Å X-ray free electron laser dataset, of natively glycosylated Env trimers complexed with BG18, the most potent V3/N332glycan-targeting bNAb reported to date. Our structures show conserved contacts mediated by common D gene-encoded residues with the N332glycan and the gp120 GDIR peptide motif, but a distinct Env-binding orientation relative to PGT121/10-1074 bNAbs. BG18’s binding orientation provides additional contacts with N392and N386glycans near the V3-loop base and engages protein components of the V1-loop. The BG18-natively-glycosylated Env structures facilitate understanding of bNAb-glycan interactions critical for using V3/N332bNAbs therapeutically and targeting their epitope for immunogen design.

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