Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity.

The inherent antigen cross-reactivity of the T cell receptor (TCR) is balanced by high specificity. Surprisingly, TCR specificity often manifests in ways not easily interpreted from static structures. Here we show that TCR discrimination between an HLA-A*03:01 (HLA-A3)-restricted public neoantigen and its wild-type (WT) counterpart emerges from distinct motions within the HLA-A3 peptide binding groove that vary with the identity of the peptide's first primary anchor. These motions create a dynamic gate that, in the presence of the WT peptide, impedes a large conformational change required for TCR binding. The neoantigen is insusceptible to this limiting dynamic, and, with the gate open, upon TCR binding the central tryptophan can transit underneath the peptide backbone to the opposing side of the HLA-A3 peptide binding groove. Our findings thus reveal a novel mechanism driving TCR specificity for a cancer neoantigen that is rooted in the dynamic and allosteric nature of peptide/MHC-I binding grooves, with implications for resolving long-standing and often confounding questions about T cell specificity.
Competing Interests: Competing interests: C.A.K. and S.S.C. are inventors of patents related to the T cell receptor (TCR) sequences featured in this manuscript and are recipients of licensing revenue from Intima Bioscience shared according to Memorial Sloan Kettering Cancer Center (MSKCC) institutional policies. C.A.K. has consulted for or is on the scientific advisory boards for Achilles Therapeutics, Affini-T Therapeutics, Aleta BioTherapeutics, Bellicum Pharmaceuticals, Bristol Myers Squibb, Catamaran Bio, Cell Design Labs, Decheng Capital, G1 Therapeutics, Klus Pharma, Obsidian Therapeutics, PACT Pharma, Roche/Genentech, Royalty Pharma, and T-knife, and is a scientific co-founder and equity holder in Affini-T Therapeutics. S.S.C. is a scientific advisor and equity holder in Affini-T Therapeutics. B.M.B. is an inventor on patents relating to differences between mutant and self in identifying immunogenic neoantigens has consulted for or received funding from Merck, Pfizer, Eureka Therapeutics, and EnaraBio, and is on the scientific advisory board of T-cure Bioscience. The other authors declare no competing interests.
(© 2025. The Author(s).)