6DKP
The complex among DMF5(alpha-D26Y, alpha-Y50A,beta-L98W) TCR, human Class I MHC HLA-A2 and MART-1(26-35)(A27L) peptide
Summary for 6DKP
| Entry DOI | 10.2210/pdb6dkp/pdb |
| Descriptor | HLA class I histocompatibility antigen, A-2 alpha chain, Beta-2-microglobulin, Melanoma antigen recognized by T-cells 1, ... (5 entities in total) |
| Functional Keywords | alpha-beta t-cell receptor, class i mhc, hla-a2, mart-1 peptide, immune system |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 5 |
| Total formula weight | 94076.59 |
| Authors | Hellman, L.M.,Singh, N.K. (deposition date: 2018-05-30, release date: 2019-04-10, Last modification date: 2023-10-11) |
| Primary citation | Hellman, L.M.,Foley, K.C.,Singh, N.K.,Alonso, J.A.,Riley, T.P.,Devlin, J.R.,Ayres, C.M.,Keller, G.L.J.,Zhang, Y.,Vander Kooi, C.W.,Nishimura, M.I.,Baker, B.M. Improving T Cell Receptor On-Target Specificity via Structure-Guided Design. Mol. Ther., 27:300-313, 2019 Cited by PubMed Abstract: T cell receptors (TCRs) have emerged as a new class of immunological therapeutics. However, though antigen specificity is a hallmark of adaptive immunity, TCRs themselves do not possess the high specificity of monoclonal antibodies. Although a necessary function of T cell biology, the resulting cross-reactivity presents a significant challenge for TCR-based therapeutic development, as it creates the potential for off-target recognition and immune toxicity. Efforts to enhance TCR specificity by mimicking the antibody maturation process and enhancing affinity can inadvertently exacerbate TCR cross-reactivity. Here we demonstrate this concern by showing that even peptide-targeted mutations in the TCR can introduce new reactivities against peptides that bear similarity to the original target. To counteract this, we explored a novel structure-guided approach for enhancing TCR specificity independent of affinity. Tested with the MART-1-specific TCR DMF5, our approach had a small but discernible impact on cross-reactivity toward MART-1 homologs yet was able to eliminate DMF5 cross-recognition of more divergent, unrelated epitopes. Our study provides a proof of principle for the use of advanced structure-guided design techniques for improving TCR specificity, and it suggests new ways forward for enhancing TCRs for therapeutic use. PubMed: 30617019DOI: 10.1016/j.ymthe.2018.12.010 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.966 Å) |
Structure validation
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