4EVN

Crystal Structure of Fab CR6261 (somatic heavy chain with germline-reverted light chain)

4EVN の概要

• エントリーDOI: 10.2210/pdb4evn/pdb
• 関連するPDBエントリー: 3GBM 3GBN
• 分子名称: Fab Heavy Chain, Fab Lambda Light Chain (2 entities in total)
• 機能のキーワード: antibody, immune system, influenza ha
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 16
• 化学式量合計: 389347.94

構造登録者

Whittle, J.R.R. (登録日: 2012-04-26, 公開日: 2012-08-29, 最終更新日: 2024-10-16)

主引用文献

Lingwood, D.,McTamney, P.M.,Yassine, H.M.,Whittle, J.R.,Guo, X.,Boyington, J.C.,Wei, C.J.,Nabel, G.J.
Structural and genetic basis for development of broadly neutralizing influenza antibodies.
Nature, 489:566-570, 2012

PubMed Abstract: Influenza viruses take a yearly toll on human life despite efforts to contain them with seasonal vaccines. These viruses evade human immunity through the evolution of variants that resist neutralization. The identification of antibodies that recognize invariant structures on the influenza haemagglutinin (HA) protein have invigorated efforts to develop universal influenza vaccines. Specifically, antibodies to the highly conserved stem region of HA neutralize diverse viral subtypes. These antibodies largely derive from a specific antibody gene, heavy-chain variable region IGHV1-69, after limited affinity maturation from their germline ancestors, but how HA stimulates naive B cells to mature and induce protective immunity is unknown. To address this question, we analysed the structural and genetic basis for their engagement and maturation into broadly neutralizing antibodies. Here we show that the germline-encoded precursors of these antibodies act as functional B-cell antigen receptors (BCRs) that initiate subsequent affinity maturation. Neither the germline precursor of a prototypic antibody, CR6261 (ref. 3), nor those of two other natural human IGHV1-69 antibodies, bound HA as soluble immunoglobulin-G (IgG). However, all three IGHV1-69 precursors engaged HA when the antibody was expressed as cell surface IgM. HA triggered BCR-associated tyrosine kinase signalling by germline transmembrane IgM. Recognition and virus neutralization was dependent solely on the heavy chain, and affinity maturation of CR6261 required only seven amino acids in the complementarity-determining region (CDR) H1 and framework region 3 (FR3) to restore full activity. These findings provide insight into the initial events that lead to the generation of broadly neutralizing antibodies to influenza, informing the rational design of vaccines to elicit such antibodies and providing a model relevant to other infectious diseases, including human immunodeficiency virus/AIDS. The data further suggest that selected immunoglobulin genes recognize specific protein structural 'patterns' that provide a substrate for further affinity maturation.

PubMed: 22932267
DOI: 10.1038/nature11371

実験手法

X-RAY DIFFRACTION (2.851 Å)