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HLA-A*0201 与 Melan-A/MART-1(26(27L)-35) 肽模拟物复合物的晶体结构揭示了构象异质性，并突出了 T 细胞识别的简并性。

Crystal structures of HLA-A*0201 complexed with Melan-A/MART-1(26(27L)-35) peptidomimetics reveal conformational heterogeneity and highlight degeneracy of T cell recognition.

机构信息

Institut des Sciences Moléculaires (UMR-CNRS 5255) and Institut Européen de Chimie et Biologie (IECB), Université de Bordeaux, 2 Rue Robert Escarpit, 33607 Pessac, France.

出版信息

J Med Chem. 2010 Oct 14;53(19):7061-6. doi: 10.1021/jm100683p.

DOI:10.1021/jm100683p
PMID:20806940
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2951488/
Abstract

There is growing interest in using tumor associated antigens presented by class I major histocompatibility complex (MHC-I) proteins as cancer vaccines. As native peptides are poorly stable in biological fluids, researchers have sought to engineer synthetic peptidomimetics with greater biostability. Here, we demonstrate that antigenic peptidomimetics of the Melan-A/MART-1(26(27L)-35) melanoma antigen adopt strikingly different conformations when bound to MHC-I, highlighting the degeneracy of T cell recognition and revealing the challenges associated with mimicking native peptide conformation.

摘要

人们对使用 I 类主要组织相容性复合体 (MHC-I) 蛋白呈递的肿瘤相关抗原作为癌症疫苗越来越感兴趣。由于天然肽在生物流体中稳定性较差，研究人员一直在寻求工程合成具有更高生物稳定性的肽模拟物。在这里，我们证明了黑色素瘤抗原 Melan-A/MART-1(26(27L)-35)的抗原肽模拟物与 MHC-I 结合时采用截然不同的构象，突出了 T 细胞识别的简并性，并揭示了模拟天然肽构象所面临的挑战。

相似文献

[1]
Crystal structures of HLA-A*0201 complexed with Melan-A/MART-1(26(27L)-35) peptidomimetics reveal conformational heterogeneity and highlight degeneracy of T cell recognition.

J Med Chem. 2010-10-14

[2]
Structures of MART-126/27-35 Peptide/HLA-A2 complexes reveal a remarkable disconnect between antigen structural homology and T cell recognition.

J Mol Biol. 2007-10-5

[3]
Synthesis and Biological Evaluation of Hapten-Clicked Analogues of The Antigenic Peptide Melan-A/MART-1.

ChemMedChem. 2020-5-6

[4]
Synthetic anticancer vaccine candidates: rational design of antigenic peptide mimetics that activate tumor-specific T-cells.

J Med Chem. 2007-4-5

[5]
Peptide-specific CD8+ T-cell evolution in vivo: response to peptide vaccination with Melan-A/MART-1.

Int J Cancer. 2002-3-20

[6]
Crystal structures of two closely related but antigenically distinct HLA-A2/melanocyte-melanoma tumor-antigen peptide complexes.

J Immunol. 2001-9-15

[7]
Improved detection of melanoma antigen-specific T cells expressing low or high levels of CD8 by HLA-A2 tetramers presenting a Melan-A/Mart-1 peptide analogue.

Int J Cancer. 2002-1-1

[8]
Identification of a public CDR3 motif and a biased utilization of T-cell receptor V beta and J beta chains in HLA-A2/Melan-A-specific T-cell clonotypes of melanoma patients.

J Transl Med. 2009-3-24

[9]
Increased immunogenicity of an anchor-modified tumor-associated antigen is due to the enhanced stability of the peptide/MHC complex: implications for vaccine design.

J Immunol. 2005-4-15

[10]
Structural basis for the presentation of tumor-associated MHC class II-restricted phosphopeptides to CD4+ T cells.

J Mol Biol. 2010-4-24

引用本文的文献

[1]
Charge-based interactions through peptide position 4 drive diversity of antigen presentation by human leukocyte antigen class I molecules.

PNAS Nexus. 2022-7-27

[2]
Synthesis and Biological Evaluation of Hapten-Clicked Analogues of The Antigenic Peptide Melan-A/MART-1.

ChemMedChem. 2020-5-6

[3]
Analysis of the affinity of influenza A virus protein epitopes for swine MHC I by a modified in vitro refolding method indicated cross-reactivity between swine and human MHC I specificities.

Immunogenetics. 2018-7-10

本文引用的文献

[1]
Processing of X-ray diffraction data collected in oscillation mode.

Methods Enzymol. 1997

[2]
T cell allorecognition via molecular mimicry.

Immunity. 2009-12-18

[3]
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Acta Crystallogr D Biol Crystallogr. 2010-1

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Germ line-governed recognition of a cancer epitope by an immunodominant human T-cell receptor.

J Biol Chem. 2009-10-2

[6]
Chemotherapy enhances vaccine-induced antitumor immunity in melanoma patients.

Int J Cancer. 2009-1-1

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Conformational changes and flexibility in T-cell receptor recognition of peptide-MHC complexes.

Biochem J. 2008-10-15

[8]
Regulation of MHC class I assembly and peptide binding.

Annu Rev Cell Dev Biol. 2008

[9]
Structures of MART-126/27-35 Peptide/HLA-A2 complexes reveal a remarkable disconnect between antigen structural homology and T cell recognition.

J Mol Biol. 2007-10-5

[10]
More than one reason to rethink the use of peptides in vaccine design.

Nat Rev Drug Discov. 2007-5

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