4qok
From Proteopedia
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| - | ''' | + | ==Structural basis for ineffective T-cell responses to MHC anchor residue improved heteroclitic peptides== |
| + | <StructureSection load='4qok' size='340' side='right' caption='[[4qok]], [[Resolution|resolution]] 3.00Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4qok]] is a 5 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QOK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QOK FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3hg1|3hg1]], [[4jfd|4jfd]]</td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4qok FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qok OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4qok RCSB], [http://www.ebi.ac.uk/pdbsum/4qok PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/B2MG_HUMAN B2MG_HUMAN]] Defects in B2M are the cause of hypercatabolic hypoproteinemia (HYCATHYP) [MIM:[http://omim.org/entry/241600 241600]]. Affected individuals show marked reduction in serum concentrations of immunoglobulin and albumin, probably due to rapid degradation.<ref>PMID:16549777</ref> Note=Beta-2-microglobulin may adopt the fibrillar configuration of amyloid in certain pathologic states. The capacity to assemble into amyloid fibrils is concentration dependent. Persistently high beta(2)-microglobulin serum levels lead to amyloidosis in patients on long-term hemodialysis.<ref>PMID:3532124</ref> <ref>PMID:1336137</ref> <ref>PMID:7554280</ref> <ref>PMID:4586824</ref> <ref>PMID:8084451</ref> <ref>PMID:12119416</ref> <ref>PMID:12796775</ref> <ref>PMID:16901902</ref> <ref>PMID:16491088</ref> <ref>PMID:17646174</ref> <ref>PMID:18835253</ref> <ref>PMID:18395224</ref> <ref>PMID:19284997</ref> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/1A02_HUMAN 1A02_HUMAN]] Involved in the presentation of foreign antigens to the immune system. [[http://www.uniprot.org/uniprot/MAR1_HUMAN MAR1_HUMAN]] Involved in melanosome biogenesis by ensuring the stability of GPR143. Plays a vital role in the expression, stability, trafficking, and processing of melanocyte protein PMEL, which is critical to the formation of stage II melanosomes.<ref>PMID:15695812</ref> <ref>PMID:19717472</ref> [[http://www.uniprot.org/uniprot/B2MG_HUMAN B2MG_HUMAN]] Component of the class I major histocompatibility complex (MHC). Involved in the presentation of peptide antigens to the immune system. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | MHC anchor residue-modified 'heteroclitic' peptides have been used in many cancer vaccine trials and often induce greater immune responses than those by the wildtype peptide. The best-studied system to date is the decamer MART-1/Melan-A26-35 peptide, EAAGIGILTV, where the natural alanine at position 2 has been modified to leucine to improve human leukocyte antigen (HLA)-A*0201 anchoring. The resulting ELAGIGILTV peptide has been used in many studies. We recently showed that T cells primed with the ELAGIGILTV peptide can fail to recognize the natural tumor-expressed peptide efficiently, thereby providing a potential molecular reason for why clinical trials of this peptide have been unsuccessful. Here, we solved the structure of a T-cell receptor (TCR) in complex with wildtype peptide and compared it with its heteroclitic counterpart. The data demonstrate that a suboptimal anchor residue at position 2 enables the TCR to 'pull' the peptide away from the MHC binding groove, facilitating extra contacts with both the peptide and MHC surface. These data explain how a TCR can distinguish between two epitopes and demonstrate how weak MHC anchoring can enable an induced-fit interaction with the TCR. Our findings constitute a novel demonstration of the extreme sensitivity of the TCR to minor alterations in peptide conformation. This article is protected by copyright. All rights reserved. | ||
| - | + | Structural basis for ineffective T-cell responses to MHC anchor residue-improved 'heteroclitic' peptides.,Madura F, Rizkallah PJ, Holland CJ, Fuller A, Bulek A, Godkin AJ, Schauenburg AJ, Cole DK, Sewell AK Eur J Immunol. 2014 Dec 4. doi: 10.1002/eji.201445114. PMID:25471691<ref>PMID:25471691</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | == References == | |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Cole, D K]] | ||
| + | [[Category: Madura, F]] | ||
| + | [[Category: Rizkallah, P J]] | ||
| + | [[Category: Sewell, A K]] | ||
| + | [[Category: Hla]] | ||
| + | [[Category: Immune system]] | ||
| + | [[Category: Immunoglobulin]] | ||
| + | [[Category: Melanoma]] | ||
| + | [[Category: Tcr]] | ||
Revision as of 12:42, 17 December 2014
Structural basis for ineffective T-cell responses to MHC anchor residue improved heteroclitic peptides
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Categories: Cole, D K | Madura, F | Rizkallah, P J | Sewell, A K | Hla | Immune system | Immunoglobulin | Melanoma | Tcr
