6D78

The complex between high-affinity TCR DMF5(alpha-D26Y,beta-L98W) and human Class I MHC HLA-A2 with the bound MART-1(27-35)peptide

Summary for 6D78

• Entry DOI: 10.2210/pdb6d78/pdb
• Descriptor: HLA class I histocompatibility antigen, A-2 alpha chain, Beta-2-microglobulin, Melanoma antigen recognized by T-cells 1, ... (6 entities in total)
• Functional Keywords: alpha-beta t-cell receptor bound to class i mhc (hla-a2) in complex with the mart-1 peptide, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 5
• Total formula weight: 93997.49

Authors

Hellman, L.M.,Singh, N.K. (deposition date: 2018-04-24, release date: 2019-04-03, Last modification date: 2024-10-30)

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

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: 30617019
DOI: 10.1016/j.ymthe.2018.12.010

Experimental method

X-RAY DIFFRACTION (2.347 Å)