6px6: Difference between revisions
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The | ==HLA-TCR complex== | ||
<StructureSection load='6px6' size='340' side='right'caption='[[6px6]], [[Resolution|resolution]] 3.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6px6]] is a 5 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=6PX6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PX6 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]] 3.0000033Å</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=6px6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6px6 OCA], [https://pdbe.org/6px6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6px6 RCSB], [https://www.ebi.ac.uk/pdbsum/6px6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6px6 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q08AS3_HUMAN Q08AS3_HUMAN] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The highly homologous human leukocyte antigen (HLA)-DQ2 molecules, HLA-DQ2.5 and HLA-DQ2.2, are implicated in the pathogenesis of celiac disease (CeD) by presenting gluten peptides to CD4(+) T cells. However, while HLA-DQ2.5 is strongly associated with disease, HLA-DQ2.2 is not, and the molecular basis underpinning this differential disease association is unresolved. We here provide structural evidence for how the single polymorphic residue (HLA-DQ2.5-Tyr22alpha and HLA-DQ2.2-Phe22alpha) accounts for HLA-DQ2.2 additionally requiring gluten epitopes possessing a serine at the P3 position of the peptide. In marked contrast to the biased T cell receptor (TCR) usage associated with HLA-DQ2.5-mediated CeD, we demonstrate with extensive single-cell sequencing that a diverse TCR repertoire enables recognition of the immunodominant HLA-DQ2.2-glut-L1 epitope. The crystal structure of two CeD patient-derived TCR in complex with HLA-DQ2.2 and DQ2.2-glut-L1 (PFSEQEQPV) revealed a docking strategy, and associated interatomic contacts, which was notably distinct from the structures of the TCR:HLA-DQ2.5:gliadin epitope complexes. Accordingly, while the molecular surfaces of the antigen-binding clefts of HLA-DQ2.5 and HLA-DQ2.2 are very similar, differences in the nature of the peptides presented translates to differences in responding T cell repertoires and the nature of engagement of the respective antigen-presenting molecules, which ultimately is associated with differing disease penetrance. | |||
A molecular basis for the T cell response in HLA-DQ2.2 mediated celiac disease.,Ting YT, Dahal-Koirala S, Kim HSK, Qiao SW, Neumann RS, Lundin KEA, Petersen J, Reid HH, Sollid LM, Rossjohn J Proc Natl Acad Sci U S A. 2020 Jan 23. pii: 1914308117. doi:, 10.1073/pnas.1914308117. PMID:31974305<ref>PMID:31974305</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6px6" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[MHC 3D structures|MHC 3D structures]] | |||
*[[MHC I 3D structures|MHC I 3D structures]] | |||
*[[T-cell receptor 3D structures|T-cell receptor 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Triticum aestivum]] | |||
[[Category: Reid HH]] | |||
[[Category: Rossjohn J]] | |||
[[Category: Ting YT]] | |||
Latest revision as of 10:37, 11 October 2023
HLA-TCR complexHLA-TCR complex
Structural highlights
FunctionPublication Abstract from PubMedThe highly homologous human leukocyte antigen (HLA)-DQ2 molecules, HLA-DQ2.5 and HLA-DQ2.2, are implicated in the pathogenesis of celiac disease (CeD) by presenting gluten peptides to CD4(+) T cells. However, while HLA-DQ2.5 is strongly associated with disease, HLA-DQ2.2 is not, and the molecular basis underpinning this differential disease association is unresolved. We here provide structural evidence for how the single polymorphic residue (HLA-DQ2.5-Tyr22alpha and HLA-DQ2.2-Phe22alpha) accounts for HLA-DQ2.2 additionally requiring gluten epitopes possessing a serine at the P3 position of the peptide. In marked contrast to the biased T cell receptor (TCR) usage associated with HLA-DQ2.5-mediated CeD, we demonstrate with extensive single-cell sequencing that a diverse TCR repertoire enables recognition of the immunodominant HLA-DQ2.2-glut-L1 epitope. The crystal structure of two CeD patient-derived TCR in complex with HLA-DQ2.2 and DQ2.2-glut-L1 (PFSEQEQPV) revealed a docking strategy, and associated interatomic contacts, which was notably distinct from the structures of the TCR:HLA-DQ2.5:gliadin epitope complexes. Accordingly, while the molecular surfaces of the antigen-binding clefts of HLA-DQ2.5 and HLA-DQ2.2 are very similar, differences in the nature of the peptides presented translates to differences in responding T cell repertoires and the nature of engagement of the respective antigen-presenting molecules, which ultimately is associated with differing disease penetrance. A molecular basis for the T cell response in HLA-DQ2.2 mediated celiac disease.,Ting YT, Dahal-Koirala S, Kim HSK, Qiao SW, Neumann RS, Lundin KEA, Petersen J, Reid HH, Sollid LM, Rossjohn J Proc Natl Acad Sci U S A. 2020 Jan 23. pii: 1914308117. doi:, 10.1073/pnas.1914308117. PMID:31974305[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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