1TVB

Crystal structure of Melanoma Antigen gp100(209-217) Bound to Human Class I MHC HLA-A2

1TVB の概要

• エントリーDOI: 10.2210/pdb1tvb/pdb
• 関連するPDBエントリー: 1DUZ 1QR1 1TVH
• 分子名称: HLA class I histocompatibility antigen, A-2 alpha chain, Beta-2-microglobulin, epitope of Melanocyte protein Pmel 17, ... (5 entities in total)
• 機能のキーワード: melanoma; x-ray; gp100; peptide; mhc; hla-a2, immune system
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P01892; Secreted: P61769; Endoplasmic reticulum membrane; Single-pass type I membrane protein. M-alpha: Secreted: P40967
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 91503.43

構造登録者

Borbulevych, O.Y.,Baker, B.M. (登録日: 2004-06-29, 公開日: 2005-04-19, 最終更新日: 2024-10-30)

主引用文献

Borbulevych, O.Y.,Baxter, T.K.,Yu, Z.,Restifo, N.P.,Baker, B.M.
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., 174:4812-4820, 2005

PubMed Abstract: The use of "anchor-fixed" altered peptide ligands is of considerable interest in the development of therapeutic vaccines for cancer and infectious diseases, but the mechanism by which successful altered peptide ligands elicit enhanced immunity is unclear. In this study, we have determined the crystallographic structure of a major tumor rejection Ag, gp100(209-217), in complex with the HLA-A*0201 (HLA-A2) molecule, as well as the structure of a modified version of the peptide which substitutes methionine for threonine at position 2 (T2M; gp100(209-2M)). The T2M-modified peptide, which is more immunogenic in vitro and in vivo, binds HLA-A2 with a approximately 9-fold greater affinity and has a approximately 7-fold slower dissociation rate at physiological temperature. Within the limit of the crystallographic data, the T2M substitution does not alter the structure of the peptide/HLA-A2 complex. Consistent with this finding, in peripheral blood from 95 human subjects, we were unable to identify higher frequencies of T cells specific for either the native or modified peptide. These data strongly support the conclusion that the greater immunogenicity of the gp100(209-2M) peptide is due to the enhanced stability of the peptide/MHC complex, validating the anchor-fixing approach for generating therapeutic vaccine candidates. Thermodynamic data suggest that the enhanced stability of the T2M-modified peptide/HLA-A2 complex is attributable to the increased hydrophobicity of the modified peptide, but the gain due to hydrophobicity is offset considerably by the loss of a hydrogen bond made by the native peptide to the HLA-A2 molecule. Our findings have broad implications for the optimization of current vaccine-design strategies.

PubMed: 15814707

実験手法

X-RAY DIFFRACTION (1.8 Å)