2guo: Difference between revisions
New page: left|200px<br /> <applet load="2guo" size="450" color="white" frame="true" align="right" spinBox="true" caption="2guo, resolution 1.90Å" /> '''Human Class I MHC H... |
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caption="2guo, resolution 1.90Å" /> | caption="2guo, resolution 1.90Å" /> | ||
'''Human Class I MHC HLA-A2 in complex with the native nonameric Melan-A/MART-1(27-35) peptide'''<br /> | '''Human Class I MHC HLA-A2 in complex with the native nonameric Melan-A/MART-1(27-35) peptide'''<br /> | ||
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==Overview== | ==Overview== | ||
Small structural changes in peptides presented by major histocompatibility, complex (MHC) molecules often result in large changes in immunogenicity, supporting the notion that T cell receptors are exquisitely sensitive to, antigen structure. Yet there are striking examples of TCR recognition of, structurally dissimilar ligands. The resulting unpredictability of how T, cells will respond to different or modified antigens impacts both our, understanding of the physical bases for TCR specificity as well as efforts, to engineer peptides for immunomodulation. In cancer immunotherapy, epitopes and variants derived from the MART-1/Melan-A protein are widely, used as clinical vaccines. Two overlapping epitopes spanning amino acid, residues 26 through 35 are of particular interest: numerous clinical, studies have been performed using variants of the MART-1 26-35 decamer, although only the 27-35 nonamer has been found on the surface of targeted, melanoma cells. Here, we show that the 26-35 and 27-35 peptides adopt, strikingly different conformations when bound to HLA-A2. Nevertheless, clonally distinct MART-1(26/27-35)-reactive T cells show broad, cross-reactivity towards these ligands. Simultaneously, however, many of, the cross-reactive T cells remain unable to recognize anchor-modified, variants with very subtle structural differences. These dichotomous, observations challenge our thinking about how structural information on, unligated peptide/MHC complexes should be best used when addressing, questions of TCR specificity. Our findings also indicate that caution is, warranted in the design of immunotherapeutics based on the MART-1 26/27-35, epitopes, as neither cross-reactivity nor selectivity is predictable based, on the analysis of the structures alone. | Small structural changes in peptides presented by major histocompatibility, complex (MHC) molecules often result in large changes in immunogenicity, supporting the notion that T cell receptors are exquisitely sensitive to, antigen structure. Yet there are striking examples of TCR recognition of, structurally dissimilar ligands. The resulting unpredictability of how T, cells will respond to different or modified antigens impacts both our, understanding of the physical bases for TCR specificity as well as efforts, to engineer peptides for immunomodulation. In cancer immunotherapy, epitopes and variants derived from the MART-1/Melan-A protein are widely, used as clinical vaccines. Two overlapping epitopes spanning amino acid, residues 26 through 35 are of particular interest: numerous clinical, studies have been performed using variants of the MART-1 26-35 decamer, although only the 27-35 nonamer has been found on the surface of targeted, melanoma cells. Here, we show that the 26-35 and 27-35 peptides adopt, strikingly different conformations when bound to HLA-A2. Nevertheless, clonally distinct MART-1(26/27-35)-reactive T cells show broad, cross-reactivity towards these ligands. Simultaneously, however, many of, the cross-reactive T cells remain unable to recognize anchor-modified, variants with very subtle structural differences. These dichotomous, observations challenge our thinking about how structural information on, unligated peptide/MHC complexes should be best used when addressing, questions of TCR specificity. Our findings also indicate that caution is, warranted in the design of immunotherapeutics based on the MART-1 26/27-35, epitopes, as neither cross-reactivity nor selectivity is predictable based, on the analysis of the structures alone. | ||
==About this Structure== | ==About this Structure== | ||
2GUO is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NA and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | 2GUO is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NA:'>NA</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GUO OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: x-ray crystallography]] | [[Category: x-ray crystallography]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 13:06:37 2008'' | ||
Revision as of 14:06, 23 January 2008
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Human Class I MHC HLA-A2 in complex with the native nonameric Melan-A/MART-1(27-35) peptide
OverviewOverview
Small structural changes in peptides presented by major histocompatibility, complex (MHC) molecules often result in large changes in immunogenicity, supporting the notion that T cell receptors are exquisitely sensitive to, antigen structure. Yet there are striking examples of TCR recognition of, structurally dissimilar ligands. The resulting unpredictability of how T, cells will respond to different or modified antigens impacts both our, understanding of the physical bases for TCR specificity as well as efforts, to engineer peptides for immunomodulation. In cancer immunotherapy, epitopes and variants derived from the MART-1/Melan-A protein are widely, used as clinical vaccines. Two overlapping epitopes spanning amino acid, residues 26 through 35 are of particular interest: numerous clinical, studies have been performed using variants of the MART-1 26-35 decamer, although only the 27-35 nonamer has been found on the surface of targeted, melanoma cells. Here, we show that the 26-35 and 27-35 peptides adopt, strikingly different conformations when bound to HLA-A2. Nevertheless, clonally distinct MART-1(26/27-35)-reactive T cells show broad, cross-reactivity towards these ligands. Simultaneously, however, many of, the cross-reactive T cells remain unable to recognize anchor-modified, variants with very subtle structural differences. These dichotomous, observations challenge our thinking about how structural information on, unligated peptide/MHC complexes should be best used when addressing, questions of TCR specificity. Our findings also indicate that caution is, warranted in the design of immunotherapeutics based on the MART-1 26/27-35, epitopes, as neither cross-reactivity nor selectivity is predictable based, on the analysis of the structures alone.
About this StructureAbout this Structure
2GUO is a Protein complex structure of sequences from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Structures of MART-1(26/27-35) Peptide/HLA-A2 Complexes Reveal a Remarkable Disconnect between Antigen Structural Homology and T Cell Recognition., Borbulevych OY, Insaidoo FK, Baxter TK, Powell DJ Jr, Johnson LA, Restifo NP, Baker BM, J Mol Biol. 2007 Oct 5;372(5):1123-36. Epub 2007 Jul 26. PMID:17719062
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