4GRM
The crystal structure of the high affinity TCR A6
Summary for 4GRM
| Entry DOI | 10.2210/pdb4grm/pdb |
| Related | 3QH3 |
| Descriptor | A6 alpha chain, A6 beta chain (3 entities in total) |
| Functional Keywords | high-affinity tcr, c134 modification, tax peptide, nonapeptide, mhc class i, hla-a2, tcr a6, cross-reactivity, immune system |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 97696.00 |
| Authors | Borbulevych, O.Y.,Scott, D.R.,Baker, B.M. (deposition date: 2012-08-25, release date: 2013-07-10, Last modification date: 2024-10-16) |
| Primary citation | 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 Cited by 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: 23805144DOI: 10.3389/fimmu.2013.00168 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
Download full validation report
