7KKZ

Crystal structure of mouse anti-HIV potent neutralizing antibody M4H2K1

7KKZ の概要

• エントリーDOI: 10.2210/pdb7kkz/pdb
• 分子名称: Light chain of Fab fragment of mouse monoclonal antibody M4H2K1, Heavy chain of Fab fragment of mouse monoclonal antibody M4H2K1, 2-[N-CYCLOHEXYLAMINO]ETHANE SULFONIC ACID, ... (5 entities in total)
• 機能のキーワード: hiv-1, env, monoclonal antibody, immune system, antiviral protein
• 由来する生物種: Mus musculus; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 48291.02

構造登録者

Kumar, S.,Wilson, I.A. (登録日: 2020-10-28, 公開日: 2021-07-07, 最終更新日: 2024-11-13)

主引用文献

Kumar, S.,Lin, X.,Ngo, T.,Shapero, B.,Sou, C.,Allen, J.D.,Copps, J.,Zhang, L.,Ozorowski, G.,He, L.,Crispin, M.,Ward, A.B.,Wilson, I.A.,Zhu, J.
Neutralizing Antibodies Induced by First-Generation gp41-Stabilized HIV-1 Envelope Trimers and Nanoparticles.
Mbio, 12:e0042921-e0042921, 2021

PubMed Abstract: The immunogenicity of gp41-stabilized HIV-1 BG505 envelope (Env) trimers and nanoparticles (NPs) was recently assessed in mice and rabbits. Here, we combined Env-specific B-cell sorting and repertoire sequencing to identify neutralizing antibodies (NAbs) from immunized animals. A panel of mouse NAbs was isolated from mice immunized with a 60-meric I3-01 NP presenting 20 stabilized trimers. Three mouse NAbs potently neutralized BG505.T332N by recognizing a glycan epitope centered in the C3/V4 region on BG505 Env, as revealed by electron microscopy (EM), X-ray crystallography, and epitope mapping. A set of rabbit NAbs was isolated from rabbits immunized with a soluble trimer and a 24-meric ferritin NP presenting 8 trimers. Neutralization assays against BG505.T332N variants confirmed that potent rabbit NAbs targeted previously described glycan holes on BG505 Env and accounted for a significant portion of the autologous NAb response in both the trimer and ferritin NP groups. Last, we examined NAb responses that were induced by non-BG505 Env immunogens. We determined a 3.4-Å-resolution crystal structure for the clade C transmitted/founder (T/F) Du172.17 Env with a redesigned heptad repeat 1 (HR1) bend in gp41. This clade C Env, in a soluble trimer form and in a multivalent form with 8 trimers attached to ferritin NP, and the gp41-stabilized clade A Q482-d12 Env trimer elicited distinct NAb responses in rabbits, with notable differences in neutralization breadth. Although eliciting a broad NAb response remains a major challenge, our study provides valuable information on an HIV-1 vaccine design strategy that combines gp41 stabilization and NP display. Self-assembling protein nanoparticles (NPs) presenting BG505 envelope (Env) trimers can elicit tier 2 HIV-1-neutralizing antibody (NAb) responses more effectively than soluble trimers. In the present study, monoclonal NAbs were isolated from previously immunized mice and rabbits for structural and functional analyses, which revealed that potent mouse NAbs recognize the C3/V4 region and small NP-elicited rabbit NAbs primarily target known glycan holes on BG505 Env. This study validates the gp41 stabilization strategy for HIV-1 Env vaccine design and highlights the challenge in eliciting a broad NAb response.

PubMed: 34156262
DOI: 10.1128/mBio.00429-21

実験手法

X-RAY DIFFRACTION (1.5 Å)