2ddq
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(New page: 200px<br /> <applet load="2ddq" size="450" color="white" frame="true" align="right" spinBox="true" caption="2ddq, resolution 2.35Å" /> '''Crystal Structure o...)
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Revision as of 07:41, 18 November 2007
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Crystal Structure of the Fab fragment of a R310 antibody complexed with (R)-HNE-histidine adduct
Overview
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.
About this Structure
2DDQ is a Protein complex structure of sequences from Mus musculus with EPE and HRB as ligands. Full crystallographic information is available from OCA.
Reference
Bispecific abs against modified protein and DNA with oxidized lipids., 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, Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6160-5. Epub 2006 Apr 7. PMID:16603628
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