9B44

Crystal structure of mAb 8-24 Fab, a VRC01-like HIV-1 antibody

9B44 の概要

• エントリーDOI: 10.2210/pdb9b44/pdb
• 分子名称: MLK8-24 Fab Heavy Chain, MLK8-24 Fab Light Chain, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: hiv antibody, immune system
• 由来する生物種: Mus musculus; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 99194.40

構造登録者

Kher, G.,Hurlburt, N.,Pancera, M. (登録日: 2024-03-20, 公開日: 2024-09-04, 最終更新日: 2025-03-26)

主引用文献

Agrawal, P.,Knudsen, M.L.,MacCamy, A.,Hurlburt, N.K.,Khechaduri, A.,Salladay, K.R.,Kher, G.M.,Kallur Siddaramaiah, L.,Stuart, A.B.,Bontjer, I.,Shen, X.,Montefiori, D.,Gristick, H.B.,Bjorkman, P.J.,Sanders, R.W.,Pancera, M.,Stamatatos, L.
Short CDRL1 in intermediate VRC01-like mAbs is not sufficient to overcome key glycan barriers on HIV-1 Env.
J.Virol., 98:e0074424-e0074424, 2024

PubMed Abstract: VRC01-class broadly neutralizing antibodies (bnAbs) have been isolated from people with HIV-1, but they have not yet been elicited by vaccination. They are extensively somatically mutated and sometimes accumulate CDRL1 deletions. Such indels may allow VRC01-class antibodies to accommodate the glycans expressed on a conserved N276 N-linked glycosylation site in loop D of the gp120 subunit. These glycans constitute a major obstacle in the development of VRC01-class antibodies, as unmutated antibody forms are unable to accommodate them. Although immunizations of knock-in mice expressing human VRC01-class B-cell receptors (BCRs) with specifically designed Env-derived immunogens lead to the accumulation of somatic mutations in VRC01-class BCRs, CDRL1 deletions are rarely observed, and the elicited antibodies display narrow neutralizing activities. The lack of broad neutralizing potential could be due to the absence of deletions, the lack of appropriate somatic mutations, or both. To address this point, we modified our previously determined prime-boost immunization with a germline-targeting immunogen nanoparticle (426c.Mod.Core), followed by a heterologous core nanoparticle (HxB2.WT.Core), by adding a final boost with a cocktail of various stabilized soluble Env trimers. We isolated VRC01-like antibodies with extensive somatic mutations and, in one case, a seven-amino acid CDRL1 deletion. We generated chimeric antibodies that combine the vaccine-elicited somatic mutations with CDRL1 deletions present in human mature VRC01 bnAbs. We observed that CDRL1 indels did not improve the neutralizing antibody activities. Our study indicates that CDRL1 length by itself is not sufficient for the broadly neutralizing phenotype of this class of antibodies.

PubMed: 39240111
DOI: 10.1128/jvi.00744-24

実験手法

X-RAY DIFFRACTION (2.01 Å)