4L3E

The complex between high affinity TCR DMF5(alpha-D26Y,beta-L98W) and human Class I MHC HLA-A2 with the bound MART-1(26-35)(A27L) peptide

4L3E の概要

• エントリーDOI: 10.2210/pdb4l3e/pdb
• 関連するPDBエントリー: 3QDG 3QDJ 3QDM 3QEQ 3QEU
• 分子名称: HLA class I histocompatibility antigen, A-2 alpha chain, Beta-2-microglobulin, Melanoma antigen recognized by T-cells 1, ... (6 entities in total)
• 機能のキーワード: receptors, membrane, 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 III membrane protein: Q16655
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 93775.09

構造登録者

Hellman, L.M. (登録日: 2013-06-05, 公開日: 2014-06-11, 最終更新日: 2024-10-30)

主引用文献

Pierce, B.G.,Hellman, L.M.,Hossain, M.,Singh, N.K.,Vander Kooi, C.W.,Weng, Z.,Baker, B.M.
Computational design of the affinity and specificity of a therapeutic T cell receptor.
PLOS COMPUT.BIOL., 10:e1003478-e1003478, 2014

PubMed Abstract: T cell receptors (TCRs) are key to antigen-specific immunity and are increasingly being explored as therapeutics, most visibly in cancer immunotherapy. As TCRs typically possess only low-to-moderate affinity for their peptide/MHC (pMHC) ligands, there is a recognized need to develop affinity-enhanced TCR variants. Previous in vitro engineering efforts have yielded remarkable improvements in TCR affinity, yet concerns exist about the maintenance of peptide specificity and the biological impacts of ultra-high affinity. As opposed to in vitro engineering, computational design can directly address these issues, in theory permitting the rational control of peptide specificity together with relatively controlled increments in affinity. Here we explored the efficacy of computational design with the clinically relevant TCR DMF5, which recognizes nonameric and decameric epitopes from the melanoma-associated Melan-A/MART-1 protein presented by the class I MHC HLA-A2. We tested multiple mutations selected by flexible and rigid modeling protocols, assessed impacts on affinity and specificity, and utilized the data to examine and improve algorithmic performance. We identified multiple mutations that improved binding affinity, and characterized the structure, affinity, and binding kinetics of a previously reported double mutant that exhibits an impressive 400-fold affinity improvement for the decameric pMHC ligand without detectable binding to non-cognate ligands. The structure of this high affinity mutant indicated very little conformational consequences and emphasized the high fidelity of our modeling procedure. Overall, our work showcases the capability of computational design to generate TCRs with improved pMHC affinities while explicitly accounting for peptide specificity, as well as its potential for generating TCRs with customized antigen targeting capabilities.

PubMed: 24550723
DOI: 10.1371/journal.pcbi.1003478

実験手法

X-RAY DIFFRACTION (2.557 Å)