Solution mapping of MHC-I:TCR interactions using a minimalistic protein system
Recognition of epitopic peptide antigens presented on class I major histocompatibility complex (MHC-I) proteins by T cell receptors (TCRs) forms the cornerstone of immune surveillance, leading to a plethora of adaptive immune responses. Characterization of TCR:peptide/MHC-I interactions is critical for understanding immune recognition, and developing immunotherapies, but the large variation in docking orientations of TCRs on their peptide/MHC-I targets challenges structural modeling. NMR spectroscopy could potentially resolve this ambiguity, but the large size of the TCR:peptide/MHC-I complex limits data quality. Here, we demonstrate that a designed MHC-I protein, SMART A*02:01, enables facile solution mapping of MHC-I:TCR interactions at scale. Our approach can be combined with computational modeling and structure-guided engineering to aid the development of TCR-based therapeutics.
Authors
- K. Christopher García (ORCID: https://orcid.org/0000-0001-9273-0278)
- Nikolaos G. Sgourakis (ORCID: https://orcid.org/0000-0003-3655-3902)
- David A. Baker (ORCID: https://orcid.org/0000-0001-7896-6217)
- Claire H. Woodward (ORCID: https://orcid.org/0000-0002-0373-6318)
- Apala Chaudhuri (ORCID: https://orcid.org/0000-0003-2669-850X)
- Xiaojing Chen (ORCID: https://orcid.org/0000-0002-5614-1406)
- William L. White (ORCID: https://orcid.org/0009-0004-0041-2125)
Institutions
- Children's Hospital of Philadelphia (US)
- University of Washington (US)
- University of Pennsylvania (US)
- Stanford University (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-06-09
- DOI
- https://doi.org/10.1073/pnas.2506016122
- Citations
- 1
- Primary Topic
- Monoclonal and Polyclonal Antibodies Research
- Type
- article
- Field-Weighted Citation Impact
- 1.36
Funders
- Howard Hughes Medical Institute
- Children's Hospital of Philadelphia
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- University of Pennsylvania
- Mark Foundation For Cancer Research
- Cancer Research UK
- National Institutes of Health
- National Cancer Institute
- National Institute of General Medical Sciences