Publications

Solution mapping of MHC-I:TCR interactions using a minimalistic protein system

Woodward CH, Chaudhuri A, Chen XT, White WL, Garcia KC, Baker D, Sgourakis NG. Solution mapping of MHC-I:TCR interactions using a minimalistic protein system. Proc Natl Acad Sci U S A. 2025 Jun 17;122(24):e2506016122. doi: 10.1073/pnas.2506016122. Epub 2025 Jun 9. PMID: 40489613.

 

Abstract

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.