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 neo...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56004-8 |
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| author | Jiaqi Ma Cory M. Ayres Chad A. Brambley Smita S. Chandran Tatiana J. Rosales W. W. J. Gihan Perera Bassant Eldaly William T. Murray Steven A. Corcelli Evgenii L. Kovrigin Christopher A. Klebanoff Brian M. Baker |
| author_facet | Jiaqi Ma Cory M. Ayres Chad A. Brambley Smita S. Chandran Tatiana J. Rosales W. W. J. Gihan Perera Bassant Eldaly William T. Murray Steven A. Corcelli Evgenii L. Kovrigin Christopher A. Klebanoff Brian M. Baker |
| author_sort | Jiaqi Ma |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d3f12197789e4ce3809309afbca6746f |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d3f12197789e4ce3809309afbca6746f2025-01-26T12:40:20ZengNature PortfolioNature Communications2041-17232025-01-0116112110.1038/s41467-025-56004-8Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivityJiaqi Ma0Cory M. Ayres1Chad A. Brambley2Smita S. Chandran3Tatiana J. Rosales4W. W. J. Gihan Perera5Bassant Eldaly6William T. Murray7Steven A. Corcelli8Evgenii L. Kovrigin9Christopher A. Klebanoff10Brian M. Baker11Department of Chemistry and Biochemistry, University of Notre DameDepartment of Chemistry and Biochemistry, University of Notre DameDepartment of Chemistry and Biochemistry, University of Notre DameHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC)Department of Chemistry and Biochemistry, University of Notre DameDepartment of Chemistry and Biochemistry, University of Notre DameDepartment of Chemistry and Biochemistry, University of Notre DameHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC)Department of Chemistry and Biochemistry, University of Notre DameDepartment of Chemistry and Biochemistry, University of Notre DameHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC)Department of Chemistry and Biochemistry, University of Notre DameAbstract 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.https://doi.org/10.1038/s41467-025-56004-8 |
| spellingShingle | Jiaqi Ma Cory M. Ayres Chad A. Brambley Smita S. Chandran Tatiana J. Rosales W. W. J. Gihan Perera Bassant Eldaly William T. Murray Steven A. Corcelli Evgenii L. Kovrigin Christopher A. Klebanoff Brian M. Baker Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity Nature Communications |
| title | Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity |
| title_full | Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity |
| title_fullStr | Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity |
| title_full_unstemmed | Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity |
| title_short | Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity |
| title_sort | dynamic allostery in the peptide mhc complex enables tcr neoantigen selectivity |
| url | https://doi.org/10.1038/s41467-025-56004-8 |
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