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==Crystal structure of anti-gliadin 1002-1E01 Fab fragment in complex of peptide PLQPEQPFP== | |||
<StructureSection load='5ifj' size='340' side='right'caption='[[5ifj]], [[Resolution|resolution]] 2.35Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5ifj]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Triticum_aestivum Triticum aestivum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IFJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5IFJ FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.35Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5ifj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ifj OCA], [https://pdbe.org/5ifj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ifj RCSB], [https://www.ebi.ac.uk/pdbsum/5ifj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ifj ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The role of B cells and posttranslational modifications in pathogenesis of organ-specific immune diseases is increasingly envisioned but remains poorly understood, particularly in human disorders. In celiac disease, transglutaminase 2-modified (TG2-modified; deamidated) gluten peptides drive disease-specific T cell and B cell responses, and antibodies to deamidated gluten peptides are excellent diagnostic markers. Here, we substantiate by high-throughput sequencing of IGHV genes that antibodies to a disease-specific, deamidated, and immunodominant B cell epitope of gluten (PLQPEQPFP) have biased and stereotyped usage of IGHV3-23 and IGHV3-15 gene segments with modest somatic mutations. X-ray crystal structures of 2 prototype IGHV3-15/IGKV4-1 and IGHV3-23/IGLV4-69 antibodies reveal peptide interaction mainly via germline-encoded residues. In-depth mutational analysis showed restricted selection and substitution patterns at positions involved in antigen binding. While the IGHV3-15/IGKV4-1 antibody interacts with Glu5 and Gln6, the IGHV3-23/IGLV4-69 antibody interacts with Gln3, Pro4, Pro7, and Phe8 - residues involved in substrate recognition by TG2. Hence, both antibodies, despite different interaction with the epitope, recognize signatures of TG2 processing that facilitates B cell presentation of deamidated gluten peptides to T cells, thereby providing a molecular framework for the generation of these clinically important antibodies. The study provides essential insight into the pathogenic mechanism of celiac disease. | |||
Stereotyped antibody responses target posttranslationally modified gluten in celiac disease.,Snir O, Chen X, Gidoni M, du Pre MF, Zhao Y, Steinsbo O, Lundin KE, Yaari G, Sollid LM JCI Insight. 2017 Sep 7;2(17). pii: 93961. doi: 10.1172/jci.insight.93961. PMID:28878138<ref>PMID:28878138</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Snir | <div class="pdbe-citations 5ifj" style="background-color:#fffaf0;"></div> | ||
[[Category: Sollid | |||
[[Category: | ==See Also== | ||
[[Category: | *[[Albumin 3D structures|Albumin 3D structures]] | ||
[[Category: Zhao | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Triticum aestivum]] | |||
[[Category: Chen X]] | |||
[[Category: Gidoni M]] | |||
[[Category: Lundin KE]] | |||
[[Category: Snir O]] | |||
[[Category: Sollid LM]] | |||
[[Category: Steinsbo O]] | |||
[[Category: Yaari G]] | |||
[[Category: Zhao Y]] | |||
[[Category: Du Pre MF]] | |||
Latest revision as of 16:49, 30 August 2023
Crystal structure of anti-gliadin 1002-1E01 Fab fragment in complex of peptide PLQPEQPFPCrystal structure of anti-gliadin 1002-1E01 Fab fragment in complex of peptide PLQPEQPFP
Structural highlights
Publication Abstract from PubMedThe role of B cells and posttranslational modifications in pathogenesis of organ-specific immune diseases is increasingly envisioned but remains poorly understood, particularly in human disorders. In celiac disease, transglutaminase 2-modified (TG2-modified; deamidated) gluten peptides drive disease-specific T cell and B cell responses, and antibodies to deamidated gluten peptides are excellent diagnostic markers. Here, we substantiate by high-throughput sequencing of IGHV genes that antibodies to a disease-specific, deamidated, and immunodominant B cell epitope of gluten (PLQPEQPFP) have biased and stereotyped usage of IGHV3-23 and IGHV3-15 gene segments with modest somatic mutations. X-ray crystal structures of 2 prototype IGHV3-15/IGKV4-1 and IGHV3-23/IGLV4-69 antibodies reveal peptide interaction mainly via germline-encoded residues. In-depth mutational analysis showed restricted selection and substitution patterns at positions involved in antigen binding. While the IGHV3-15/IGKV4-1 antibody interacts with Glu5 and Gln6, the IGHV3-23/IGLV4-69 antibody interacts with Gln3, Pro4, Pro7, and Phe8 - residues involved in substrate recognition by TG2. Hence, both antibodies, despite different interaction with the epitope, recognize signatures of TG2 processing that facilitates B cell presentation of deamidated gluten peptides to T cells, thereby providing a molecular framework for the generation of these clinically important antibodies. The study provides essential insight into the pathogenic mechanism of celiac disease. Stereotyped antibody responses target posttranslationally modified gluten in celiac disease.,Snir O, Chen X, Gidoni M, du Pre MF, Zhao Y, Steinsbo O, Lundin KE, Yaari G, Sollid LM JCI Insight. 2017 Sep 7;2(17). pii: 93961. doi: 10.1172/jci.insight.93961. PMID:28878138[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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