2ddq: Difference between revisions

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[[Image:2ddq.gif|left|200px]]<br />

[[Image:2ddq.gif|left|200px]]<br /><applet load="2ddq" size="350" color="white" frame="true" align="right" spinBox="true"

<applet load="2ddq" size="~~450~~" color="white" frame="true" align="right" spinBox="true"

caption="2ddq, resolution 2.35Å" />

'''Crystal Structure of the Fab fragment of a R310 antibody complexed with (R)-HNE-histidine adduct'''<br />

==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.

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 [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with EPE and HRB as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://~~ispc~~.weizmann.ac.il/oca-bin/ocashort?id=2DDQ OCA].

2DDQ is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with <scene name='pdbligand=EPE:'>EPE</scene> and <scene name='pdbligand=HRB:'>HRB</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2DDQ OCA].

==Reference==

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[[Category: monoclonal antibody]]

''Page seeded by [http://~~ispc~~.weizmann.ac.il/oca OCA ] on ~~Sun Nov 18 09~~:48:~~31 2007~~''

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:57:49 2008''

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@@ Line 1: / Line 1: @@
-[[Image:2ddq.gif|left|200px]]<br />
+[[Image:2ddq.gif|left|200px]]<br /><applet load="2ddq" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="2ddq" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="2ddq, resolution 2.35&Aring;" />
 '''Crystal Structure of the Fab fragment of a R310 antibody complexed with (R)-HNE-histidine adduct'''<br />
 ==Overview==
--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.
+-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==
-DDQ is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with EPE and HRB as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2DDQ OCA].
+DDQ is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with <scene name='pdbligand=EPE:'>EPE</scene> and <scene name='pdbligand=HRB:'>HRB</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2DDQ OCA].
 ==Reference==
@@ Line 21: / Line 20: @@
 [[Category: monoclonal antibody]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Sun Nov 18 09:48:31 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:57:49 2008''