8F7Z

VRC34.01_mm28 bound to fusion peptide

Summary for 8F7Z

• Entry DOI: 10.2210/pdb8f7z/pdb
• Descriptor: HIV-1 Env Fusion Peptide, VRC34_mm28 Heavy Chain, VRC34_m228 Light Chain, ... (4 entities in total)
• Functional Keywords: fp-neutralizing antibody, fusion peptide, hiv-1, glycoprotein, viral protein, fp-targeting vaccines
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 12
• Total formula weight: 196724.32

Authors

Olia, A.S.,Kwong, P.D. (deposition date: 2022-11-21, release date: 2023-11-01, Last modification date: 2024-02-14)

Primary citation

Banach, B.B.,Pletnev, S.,Olia, A.S.,Xu, K.,Zhang, B.,Rawi, R.,Bylund, T.,Doria-Rose, N.A.,Nguyen, T.D.,Fahad, A.S.,Lee, M.,Lin, B.C.,Liu, T.,Louder, M.K.,Madan, B.,McKee, K.,O'Dell, S.,Sastry, M.,Schon, A.,Bui, N.,Shen, C.H.,Wolfe, J.R.,Chuang, G.Y.,Mascola, J.R.,Kwong, P.D.,DeKosky, B.J.
Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site.
Nat Commun, 14:7593-7593, 2023

PubMed Abstract: 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.

PubMed: 37989731
DOI: 10.1038/s41467-023-42098-5

Experimental method

X-RAY DIFFRACTION (2.7 Å)