4GRM

The crystal structure of the high affinity TCR A6

4GRM の概要

• エントリーDOI: 10.2210/pdb4grm/pdb
• 関連するPDBエントリー: 3QH3
• 分子名称: A6 alpha chain, A6 beta chain (3 entities in total)
• 機能のキーワード: high-affinity tcr, c134 modification, tax peptide, nonapeptide, mhc class i, hla-a2, tcr a6, cross-reactivity, immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 97696.00

構造登録者

Borbulevych, O.Y.,Scott, D.R.,Baker, B.M. (登録日: 2012-08-25, 公開日: 2013-07-10, 最終更新日: 2024-10-16)

主引用文献

Cole, D.K.,Sami, M.,Scott, D.R.,Rizkallah, P.J.,Borbulevych, O.Y.,Todorov, P.T.,Moysey, R.K.,Jakobsen, B.K.,Boulter, J.M.,Baker, B.M.,Li, Y.I.
Increased Peptide Contacts Govern High Affinity Binding of a Modified TCR Whilst Maintaining a Native pMHC Docking Mode.
Front Immunol, 4:168-168, 2013

PubMed Abstract: Natural T cell receptors (TCRs) generally bind to their cognate pMHC molecules with weak affinity and fast kinetics, limiting their use as therapeutic agents. Using phage display, we have engineered a high affinity version of the A6 wild-type TCR (A6wt), specific for the human leukocyte antigen (HLA-A(∗)0201) complexed with human T cell lymphotropic virus type 111-19 peptide (A2-Tax). Mutations in just 4 residues in the CDR3β loop region of the A6wt TCR were selected that improved binding to A2-Tax by nearly 1000-fold. Biophysical measurements of this mutant TCR (A6c134) demonstrated that the enhanced binding was derived through favorable enthalpy and a slower off-rate. The structure of the free A6c134 TCR and the A6c134/A2-Tax complex revealed a native binding mode, similar to the A6wt/A2-Tax complex. However, concordant with the more favorable binding enthalpy, the A6c134 TCR made increased contacts with the Tax peptide compared with the A6wt/A2-Tax complex, demonstrating a peptide-focused mechanism for the enhanced affinity that directly involved the mutated residues in the A6c134 TCR CDR3β loop. This peptide-focused enhanced TCR binding may represent an important approach for developing antigen specific high affinity TCR reagents for use in T cell based therapies.

PubMed: 23805144
DOI: 10.3389/fimmu.2013.00168

実験手法

X-RAY DIFFRACTION (2 Å)