6TMO

Structure determination of an enhanced affinity TCR, a24b17, in complex with HLA-A*02:01 presenting a MART-1 peptide, EAAGIGILTV

6TMO の概要

• エントリーDOI: 10.2210/pdb6tmo/pdb
• 分子名称: MHC class I antigen, Beta-2-microglobulin, EAAGIGILTV, ... (10 entities in total)
• 機能のキーワード: high affinity, t-cell receptor, immune system
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 95917.22

構造登録者

Rizkallah, P.J.,Cole, D.K. (登録日: 2019-12-05, 公開日: 2020-10-07, 最終更新日: 2024-11-13)

主引用文献

Crean, R.M.,MacLachlan, B.J.,Madura, F.,Whalley, T.,Rizkallah, P.J.,Holland, C.J.,McMurran, C.,Harper, S.,Godkin, A.,Sewell, A.K.,Pudney, C.R.,van der Kamp, M.W.,Cole, D.K.
Molecular Rules Underpinning Enhanced Affinity Binding of Human T Cell Receptors Engineered for Immunotherapy.
Mol Ther Oncolytics, 18:443-456, 2020

PubMed Abstract: Immuno-oncology approaches that utilize T cell receptors (TCRs) are becoming highly attractive because of their potential to target virtually all cellular proteins, including cancer-specific epitopes, via the recognition of peptide-human leukocyte antigen (pHLA) complexes presented at the cell surface. However, because natural TCRs generally recognize cancer-derived pHLAs with very weak affinities, efforts have been made to enhance their binding strength, in some cases by several million-fold. In this study, we investigated the mechanisms underpinning human TCR affinity enhancement by comparing the crystal structures of engineered enhanced affinity TCRs with those of their wild-type progenitors. Additionally, we performed molecular dynamics simulations to better understand the energetic mechanisms driving the affinity enhancements. These data demonstrate that supra-physiological binding affinities can be achieved without altering native TCR-pHLA binding modes via relatively subtle modifications to the interface contacts, often driven through the addition of buried hydrophobic residues. Individual energetic components of the TCR-pHLA interaction governing affinity enhancements were distinct and highly variable for each TCR, often resulting from additive, or knock-on, effects beyond the mutated residues. This comprehensive analysis of affinity-enhanced TCRs has important implications for the future rational design of engineered TCRs as efficacious and safe drugs for cancer treatment.

PubMed: 32913893
DOI: 10.1016/j.omto.2020.07.008

実験手法

X-RAY DIFFRACTION (2.1 Å)