Woodward Claire H, Chaudhuri Apala, Chen Xiaojing Tina, White William L, Garcia K Christopher, Baker David, Sgourakis Nikolaos G
Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
Center for Computational and Genomic Medicine and Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104.
Proc Natl Acad Sci U S A. 2025 Jun 17;122(24):e2506016122. doi: 10.1073/pnas.2506016122. Epub 2025 Jun 9.
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.
T细胞受体（TCR）识别由I类主要组织相容性复合体（MHC-I）蛋白呈递的表位肽抗原，构成了免疫监视的基石，从而引发大量适应性免疫反应。TCR与肽/MHC-I相互作用的表征对于理解免疫识别和开发免疫疗法至关重要，但TCR在其肽/MHC-I靶点上对接方向的巨大差异给结构建模带来了挑战。核磁共振光谱有可能解决这种模糊性，但TCR-肽/MHC-I复合物的大尺寸限制了数据质量。在这里，我们证明了一种设计的MHC-I蛋白SMART A*02:01能够实现大规模的MHC-I:TCR相互作用的简便溶液图谱绘制。我们的方法可以与计算建模和结构导向工程相结合，以辅助基于TCR的治疗方法的开发。
