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< | ==Structural and kinetic basis for heightened immunogenicity of T cell vaccines== | ||
<StructureSection load='2bnq' size='340' side='right'caption='[[2bnq]], [[Resolution|resolution]] 1.70Å' scene=''> | |||
You may | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2bnq]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2BNQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2BNQ 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]] 1.7Å</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=2bnq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2bnq OCA], [https://pdbe.org/2bnq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2bnq RCSB], [https://www.ebi.ac.uk/pdbsum/2bnq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2bnq ProSAT]</span></td></tr> | ||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CTG1B_HUMAN CTG1B_HUMAN] | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/bn/2bnq_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2bnq ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Analogue peptides with enhanced binding affinity to major histocompatibility class (MHC) I molecules are currently being used in cancer patients to elicit stronger T cell responses. However, it remains unclear as to how alterations of anchor residues may affect T cell receptor (TCR) recognition. We correlate functional, thermodynamic, and structural parameters of TCR-peptide-MHC binding and demonstrate the effect of anchor residue modifications of the human histocompatibility leukocyte antigens (HLA)-A2 tumor epitope NY-ESO-1(157-165)-SLLMWITQC on TCR recognition. The crystal structure of the wild-type peptide complexed with a specific TCR shows that TCR binding centers on two prominent, sequential, peptide sidechains, methionine-tryptophan. Cysteine-to-valine substitution at peptide position 9, while optimizing peptide binding to the MHC, repositions the peptide main chain and generates subtly enhanced interactions between the analogue peptide and the TCR. Binding analyses confirm tighter binding of the analogue peptide to HLA-A2 and improved soluble TCR binding. Recognition of analogue peptide stimulates faster polarization of lytic granules to the immunological synapse, reduces dependence on CD8 binding, and induces greater numbers of cross-reactive cytotoxic T lymphocyte to SLLMWITQC. These results provide important insights into heightened immunogenicity of analogue peptides and highlight the importance of incorporating structural data into the process of rational optimization of superagonist peptides for clinical trials. | |||
Structural and kinetic basis for heightened immunogenicity of T cell vaccines.,Chen JL, Stewart-Jones G, Bossi G, Lissin NM, Wooldridge L, Choi EM, Held G, Dunbar PR, Esnouf RM, Sami M, Boulter JM, Rizkallah P, Renner C, Sewell A, van der Merwe PA, Jakobsen BK, Griffiths G, Jones EY, Cerundolo V J Exp Med. 2005 Apr 18;201(8):1243-55. PMID:15837811<ref>PMID:15837811</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2bnq" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Beta-2 microglobulin 3D structures|Beta-2 microglobulin 3D structures]] | |||
*[[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: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Bossi | [[Category: Bossi G]] | ||
[[Category: Boultier | [[Category: Boultier JM]] | ||
[[Category: Cerundolo | [[Category: Cerundolo V]] | ||
[[Category: Chen | [[Category: Chen J-L]] | ||
[[Category: Choi | [[Category: Choi EML]] | ||
[[Category: Dunbar | [[Category: Dunbar PR]] | ||
[[Category: Esnouf | [[Category: Esnouf RM]] | ||
[[Category: Griffiths | [[Category: Griffiths G]] | ||
[[Category: Held | [[Category: Held G]] | ||
[[Category: Jackobsen | [[Category: Jackobsen BK]] | ||
[[Category: Jones | [[Category: Jones EY]] | ||
[[Category: Lissin | [[Category: Lissin NM]] | ||
[[Category: Renner C]] | |||
[[Category: Renner | [[Category: Rizkallah PJ]] | ||
[[Category: Rizkallah | [[Category: Sami M]] | ||
[[Category: Sami | [[Category: Sewell A]] | ||
[[Category: Sewell | [[Category: Stewart-Jones G]] | ||
[[Category: Stewart-Jones | [[Category: Wooldridge L]] | ||
[[Category: Wooldridge | [[Category: Van der Merwe PA]] | ||
[[Category: | |||
Latest revision as of 12:01, 6 November 2024
Structural and kinetic basis for heightened immunogenicity of T cell vaccinesStructural and kinetic basis for heightened immunogenicity of T cell vaccines
Structural highlights
FunctionEvolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedAnalogue peptides with enhanced binding affinity to major histocompatibility class (MHC) I molecules are currently being used in cancer patients to elicit stronger T cell responses. However, it remains unclear as to how alterations of anchor residues may affect T cell receptor (TCR) recognition. We correlate functional, thermodynamic, and structural parameters of TCR-peptide-MHC binding and demonstrate the effect of anchor residue modifications of the human histocompatibility leukocyte antigens (HLA)-A2 tumor epitope NY-ESO-1(157-165)-SLLMWITQC on TCR recognition. The crystal structure of the wild-type peptide complexed with a specific TCR shows that TCR binding centers on two prominent, sequential, peptide sidechains, methionine-tryptophan. Cysteine-to-valine substitution at peptide position 9, while optimizing peptide binding to the MHC, repositions the peptide main chain and generates subtly enhanced interactions between the analogue peptide and the TCR. Binding analyses confirm tighter binding of the analogue peptide to HLA-A2 and improved soluble TCR binding. Recognition of analogue peptide stimulates faster polarization of lytic granules to the immunological synapse, reduces dependence on CD8 binding, and induces greater numbers of cross-reactive cytotoxic T lymphocyte to SLLMWITQC. These results provide important insights into heightened immunogenicity of analogue peptides and highlight the importance of incorporating structural data into the process of rational optimization of superagonist peptides for clinical trials. Structural and kinetic basis for heightened immunogenicity of T cell vaccines.,Chen JL, Stewart-Jones G, Bossi G, Lissin NM, Wooldridge L, Choi EM, Held G, Dunbar PR, Esnouf RM, Sami M, Boulter JM, Rizkallah P, Renner C, Sewell A, van der Merwe PA, Jakobsen BK, Griffiths G, Jones EY, Cerundolo V J Exp Med. 2005 Apr 18;201(8):1243-55. PMID:15837811[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also
References
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