Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity Journal Article
| Authors: | Ma, J.; Ayres, C. M.; Brambley, C. A.; Chandran, S. S.; Rosales, T. J.; Gihan Perera, W. W. J.; Eldaly, B.; Murray, W. T.; Corcelli, S. A.; Kovrigin, E. L.; Klebanoff, C. A.; Baker, B. M. |
| Article Title: | Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity |
| Abstract: | 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. © The Author(s) 2025. |
| Keywords: | protein conformation; metabolism; gene expression; molecular dynamics; protein binding; peptide; wild type; tumor antigen; cell specificity; t lymphocyte receptor; immunology; chemistry; antigens, neoplasm; receptors, antigen, t-cell; peptides; binding site; amino acid; models, molecular; binding sites; conformational transition; cross reaction; major histocompatibility complex; x ray crystallography; nuclear magnetic resonance; lymphocyte antigen receptor; molecular model; tryptophan; allosteric regulation; allosterism; chemical binding; cell component; cancer; humans; human; article |
| Journal Title: | Nature Communications |
| Volume: | 16 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-01-20 |
| Start Page: | 849 |
| Language: | English |
| DOI: | 10.1038/s41467-025-56004-8 |
| PUBMED: | 39833157 |
| PROVIDER: | scopus |
| PMCID: | PMC11756396 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- Source: Scopus |
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