2DDQ

Crystal Structure of the Fab fragment of a R310 antibody complexed with (R)-HNE-histidine adduct

2DDQ の概要

• エントリーDOI: 10.2210/pdb2ddq/pdb
• 分子名称: R310 antibody heavy chain, R310 antibody light chain, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (5 entities in total)
• 機能のキーワード: monoclonal antibody, 4-hydroxy-2-nonenal, immunoglobulin, immune system
• 由来する生物種: Mus musculus (house mouse); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 47406.94

構造登録者

Ito, S. (登録日: 2006-02-02, 公開日: 2006-07-11, 最終更新日: 2024-11-06)

主引用文献

Akagawa, M.,Ito, S.,Toyoda, K.,Ishii, Y.,Tatsuda, E.,Shibata, T.,Yamaguchi, S.,Kawai, Y.,Ishino, K.,Kishi, Y.,Adachi, T.,Tsubata, T.,Takasaki, Y.,Hattori, N.,Matsuda, T.,Uchida, K.
Bispecific abs against modified protein and DNA with oxidized lipids
Proc.Natl.Acad.Sci.Usa, 103:6160-6165, 2006

PubMed Abstract: 4-Hydroxy-2-nonenal (HNE), a racemic mixture of 4R- and 4S-enantiomers, is a major product of lipid peroxidation and is believed to be largely responsible for the cytopathological effects observed during oxidative stress. HNE reacts with histidine to form a stable HNE-histidine Michael addition-type adduct possessing three chiral centers in the cyclic hemiacetal structure. We have previously raised the mAbs, anti-R mAb 310 and anti-S mAb S412, that enantioselectively recognized the R-HNE-histidine and R-HNE-histidine adducts, respectively, and demonstrated the presence of both epitopes in vivo. In the present study, to further investigate the anti-HNE immune response, we analyzed the variable genes and primary structure of these Abs and found that the sequence of R310 was highly homologous to anti-DNA autoantibodies, the hallmark of systemic lupus erythematosus. An x-ray crystallographic analysis of the R310 Fab fragment showed that the R-HNE-histidine adduct binds to a hydrophobic pocket in the antigen-binding site. Despite the structural identity to the anti-DNA autoantibodies, however, R310 showed only a slight crossreactivity with the native double-stranded DNA, whereas the Ab immunoreactivity was dramatically enhanced by the treatment of the DNA with 4-oxo-2-nonenal (ONE), an analog of HNE. Moreover, the 7-(2-oxo-heptyl)-substituted 1,N2-etheno-type ONE-2'-deoxynucleoside adducts were identified as alternative epitopes of R310. Molecular mimicry between the R-HNE-histidine configurational isomers and the ONE-DNA base adducts is proposed for the dual crossreactivity.

PubMed: 16603628
DOI: 10.1073/pnas.0600865103

実験手法

X-RAY DIFFRACTION (2.35 Å)