1s9w
From Proteopedia
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==Overview== | ==Overview== | ||
| - | NY-ESO-1, a commonly expressed tumor antigen of the cancer-testis family, is expressed by a wide range of tumors but not found in normal adult | + | NY-ESO-1, a commonly expressed tumor antigen of the cancer-testis family, is expressed by a wide range of tumors but not found in normal adult somatic tissue, making it an ideal cancer vaccine candidate. Peptides derived from NY-ESO-1 have shown preclinical and clinical trial promise; however, biochemical features of these peptides have complicated their formulation and led to heterogeneous immune responses. We have taken a rational approach to engineer an HLA A2-restricted NY-ESO-1-derived T cell epitope with improved formulation and immunogenicity to the wild type peptide. To accomplish this, we have solved the x-ray crystallographic structures of HLA A2 complexed to NY-ESO (157-165) and two analogues of this peptide in which the C-terminal cysteine residue has been substituted to alanine or serine. Substitution of cysteine by serine maintained peptide conformation yet reduced complex stability, resulting in poor cytotoxic T lymphocyte recognition. Conversely, substitution with alanine maintained complex stability and cytotoxic T lymphocyte recognition. Based on the structures of the three HLA A2 complexes, we incorporated 2-aminoisobutyric acid, an isostereomer of cysteine, into the epitope. This analogue is impervious to oxidative damage, cysteinylation, and dimerization of the peptide epitope upon formulation that is characteristic of the wild type peptide. Therefore, this approach has yielded a potential therapeutic molecule that satiates the hydrophobic F pocket of HLA A2 and exhibited superior immunogenicity relative to the wild type peptide. |
==Disease== | ==Disease== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
| - | [[Category: Aguilar, M | + | [[Category: Aguilar, M I.]] |
[[Category: Beddoe, T.]] | [[Category: Beddoe, T.]] | ||
[[Category: Chang, L.]] | [[Category: Chang, L.]] | ||
[[Category: Chen, Q.]] | [[Category: Chen, Q.]] | ||
[[Category: Chen, W.]] | [[Category: Chen, W.]] | ||
| - | [[Category: Dunstone, M | + | [[Category: Dunstone, M A.]] |
[[Category: Kjer-Nielsen, L.]] | [[Category: Kjer-Nielsen, L.]] | ||
[[Category: McCluskey, J.]] | [[Category: McCluskey, J.]] | ||
| - | [[Category: Purcell, A | + | [[Category: Purcell, A W.]] |
[[Category: Rossjohn, J.]] | [[Category: Rossjohn, J.]] | ||
| - | [[Category: Webb, A | + | [[Category: Webb, A I.]] |
[[Category: SO4]] | [[Category: SO4]] | ||
[[Category: immune system]] | [[Category: immune system]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:59:21 2008'' |
Revision as of 12:59, 21 February 2008
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Crystal Structure Analysis of NY-ESO-1 epitope, SLLMWITQC, in complex with HLA-A2
Contents |
Overview
NY-ESO-1, a commonly expressed tumor antigen of the cancer-testis family, is expressed by a wide range of tumors but not found in normal adult somatic tissue, making it an ideal cancer vaccine candidate. Peptides derived from NY-ESO-1 have shown preclinical and clinical trial promise; however, biochemical features of these peptides have complicated their formulation and led to heterogeneous immune responses. We have taken a rational approach to engineer an HLA A2-restricted NY-ESO-1-derived T cell epitope with improved formulation and immunogenicity to the wild type peptide. To accomplish this, we have solved the x-ray crystallographic structures of HLA A2 complexed to NY-ESO (157-165) and two analogues of this peptide in which the C-terminal cysteine residue has been substituted to alanine or serine. Substitution of cysteine by serine maintained peptide conformation yet reduced complex stability, resulting in poor cytotoxic T lymphocyte recognition. Conversely, substitution with alanine maintained complex stability and cytotoxic T lymphocyte recognition. Based on the structures of the three HLA A2 complexes, we incorporated 2-aminoisobutyric acid, an isostereomer of cysteine, into the epitope. This analogue is impervious to oxidative damage, cysteinylation, and dimerization of the peptide epitope upon formulation that is characteristic of the wild type peptide. Therefore, this approach has yielded a potential therapeutic molecule that satiates the hydrophobic F pocket of HLA A2 and exhibited superior immunogenicity relative to the wild type peptide.
Disease
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 Structure
1S9W is a Protein complex structure of sequences from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
Reference
Functional and structural characteristics of NY-ESO-1-related HLA A2-restricted epitopes and the design of a novel immunogenic analogue., Webb AI, Dunstone MA, Chen W, Aguilar MI, Chen Q, Jackson H, Chang L, Kjer-Nielsen L, Beddoe T, McCluskey J, Rossjohn J, Purcell AW, J Biol Chem. 2004 May 28;279(22):23438-46. Epub 2004 Mar 5. PMID:15004033
Page seeded by OCA on Thu Feb 21 14:59:21 2008
