6WWC

Vaccine-elicited mouse FP-targeting neutralizing antibody vFP16.02 with S48K mutation in light chain in complex with HIV fusion peptide (residue 512-519)

6WWC の概要

• エントリーDOI: 10.2210/pdb6wwc/pdb
• 分子名称: vFP16.02 antibody heavy chain, vFP16.02 antibody light chain, fusion peptide, ... (4 entities in total)
• 機能のキーワード: hiv, fusion peptide, antibody, immune system-viral protein complex, immune system/viral protein
• 由来する生物種: Mus musculus (Mouse); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 95973.11

構造登録者

Xu, K.,Wang, Y.,Kwong, P.D. (登録日: 2020-05-09, 公開日: 2021-02-24, 最終更新日: 2024-10-16)

主引用文献

Madan, B.,Zhang, B.,Xu, K.,Chao, C.W.,O'Dell, S.,Wolfe, J.R.,Chuang, G.Y.,Fahad, A.S.,Geng, H.,Kong, R.,Louder, M.K.,Nguyen, T.D.,Rawi, R.,Schon, A.,Sheng, Z.,Nimrania, R.,Wang, Y.,Zhou, T.,Lin, B.C.,Doria-Rose, N.A.,Shapiro, L.,Kwong, P.D.,DeKosky, B.J.
Mutational fitness landscapes reveal genetic and structural improvement pathways for a vaccine-elicited HIV-1 broadly neutralizing antibody.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: Vaccine-based elicitation of broadly neutralizing antibodies holds great promise for preventing HIV-1 transmission. However, the key biophysical markers of improved antibody recognition remain uncertain in the diverse landscape of potential antibody mutation pathways, and a more complete understanding of anti-HIV-1 fusion peptide (FP) antibody development will accelerate rational vaccine designs. Here we survey the mutational landscape of the vaccine-elicited anti-FP antibody, vFP16.02, to determine the genetic, structural, and functional features associated with antibody improvement or fitness. Using site-saturation mutagenesis and yeast display functional screening, we found that 1% of possible single mutations improved HIV-1 envelope trimer (Env) affinity, but generally comprised rare somatic hypermutations that may not arise frequently in vivo. We observed that many single mutations in the vFP16.02 Fab could enhance affinity >1,000-fold against soluble FP, although affinity improvements against the HIV-1 trimer were more measured and rare. The most potent variants enhanced affinity to both soluble FP and Env, had mutations concentrated in antibody framework regions, and achieved up to 37% neutralization breadth compared to 28% neutralization of the template antibody. Altered heavy- and light-chain interface angles and conformational dynamics, as well as reduced Fab thermal stability, were associated with improved HIV-1 neutralization breadth and potency. We also observed parallel sets of mutations that enhanced viral neutralization through similar structural mechanisms. These data provide a quantitative understanding of the mutational landscape for vaccine-elicited FP-directed broadly neutralizing antibody and demonstrate that numerous antigen-distal framework mutations can improve antibody function by enhancing affinity simultaneously toward HIV-1 Env and FP.

PubMed: 33649208
DOI: 10.1073/pnas.2011653118

実験手法

X-RAY DIFFRACTION (2.563 Å)