8FLW

Cryo-EM Structure of PGT145 DU303 Fab in complex with BG505 DS-SOSIP.664

8FLW の概要

• エントリーDOI: 10.2210/pdb8flw/pdb
• EMDBエントリー: 29288
• 分子名称: PGT145 DU303 Heavy, PGT145 DU303 Light, Envelope glycoprotein gp41, ... (8 entities in total)
• 機能のキーワード: cd4, hiv-1, sosip, vaccine, immune system, llama, v2 apex, therapeutic, viral protein
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 285871.07

構造登録者

Gorman, J.,Kwong, P.D. (登録日: 2022-12-22, 公開日: 2023-05-31, 最終更新日: 2024-11-20)

主引用文献

Holt, G.T.,Gorman, J.,Wang, S.,Lowegard, A.U.,Zhang, B.,Liu, T.,Lin, B.C.,Louder, M.K.,Frenkel, M.S.,McKee, K.,O'Dell, S.,Rawi, R.,Shen, C.H.,Doria-Rose, N.A.,Kwong, P.D.,Donald, B.R.
Improved HIV-1 neutralization breadth and potency of V2-apex antibodies by in silico design.
Cell Rep, 42:112711-112711, 2023

PubMed Abstract: Broadly neutralizing antibodies (bNAbs) against HIV can reduce viral transmission in humans, but an effective therapeutic will require unusually high breadth and potency of neutralization. We employ the OSPREY computational protein design software to engineer variants of two apex-directed bNAbs, PGT145 and PG9RSH, resulting in increases in potency of over 100-fold against some viruses. The top designed variants improve neutralization breadth from 39% to 54% at clinically relevant concentrations (IC < 1 μg/mL) and improve median potency (IC) by up to 4-fold over a cross-clade panel of 208 strains. To investigate the mechanisms of improvement, we determine cryoelectron microscopy structures of each variant in complex with the HIV envelope trimer. Surprisingly, we find the largest increases in breadth to be a result of optimizing side-chain interactions with highly variable epitope residues. These results provide insight into mechanisms of neutralization breadth and inform strategies for antibody design and improvement.

PubMed: 37436900
DOI: 10.1016/j.celrep.2023.112711

実験手法

ELECTRON MICROSCOPY (3.58 Å)