2gtw
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Human Class I MHC HLA-A2 in complex with the nonameric Melan-A/MART-1(27-35) peptide having A27L substitution
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.
DiseaseDisease
Known diseases associated with this structure: Abacavir hypersensitivity, susceptibility to OMIM:[142800], Ankylosing spondylitis, susceptibility to, 1 OMIM:[142800], Hypoproteinemia, hypercatabolic OMIM:[109700], Stevens-Johnson syndrome, susceptibility to OMIM:[142800]
About this StructureAbout this Structure
2GTW is a Protein complex structure of sequences from Homo sapiens with NA, GOL and FMT 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
Page seeded by OCA on Mon Nov 12 22:22:49 2007