Geometrical characterization of T cell receptor binding modes reveals class‐specific binding to maximize access to antigen

• Published in: Proteins, structure, function, and bioinformatics structure, function, and bioinformatics, 2020-03, Vol.88 (3), p.503-513
• Main Authors: Singh, Nishant K., Abualrous, Esam T., Ayres, Cory M., Noé, Frank, Gowthaman, Ragul, Pierce, Brian G., Baker, Brian M.
• Format: Article
• Language: English
• Subjects: antigen; Antigens; Binding; binding geometry; Binding Sites; Crystallography, X-Ray; Downloading; Geometry; Histocompatibility Antigens Class I - chemistry; Histocompatibility Antigens Class I - immunology; Histocompatibility Antigens Class I - metabolism; Histocompatibility Antigens Class II - chemistry; Histocompatibility Antigens Class II - immunology; Histocompatibility Antigens Class II - metabolism; Humans; Information systems; Inspection; Lymphocytes; Lymphocytes T; Major histocompatibility complex; MHC; Models, Molecular; Outliers (statistics); peptide; Peptides; Physical properties; Principal Component Analysis; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Receptors; Receptors, Antigen, T-Cell, alpha-beta - chemistry; Receptors, Antigen, T-Cell, alpha-beta - immunology; Receptors, Antigen, T-Cell, alpha-beta - metabolism; spherical coordinates; structure; T cell receptor; T cell receptors; T-Lymphocytes - chemistry; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Thermodynamics
• ISSN: 0887-3585; 1097-0134
• DOI: 10.1002/prot.25829

Recognition of antigenic peptides bound to major histocompatibility complex (MHC) proteins by αβ T cell receptors (TCRs) is a hallmark of T cell mediated immunity. Recent data suggest that variations in TCR binding geometry may influence T cell signaling, which could help explain outliers in relationships between physical parameters such as TCR‐pMHC binding affinity and T cell function. Traditionally, TCR binding geometry has been described with simple descriptors such as the crossing angle, which quantifies what has become known as the TCR's diagonal binding mode. However, these descriptors often fail to reveal distinctions in binding geometry that are apparent through visual inspection. To provide a better framework for relating TCR structure to T cell function, we developed a comprehensive system for quantifying the geometries of how TCRs bind peptide/MHC complexes. We show that our system can discern differences not clearly revealed by more common methods. As an example of its potential to impact biology, we used it to reveal differences in how TCRs bind class I and class II peptide/MHC complexes, which we show allow the TCR to maximize access to and “read out” the peptide antigen. We anticipate our system will be of use in not only exploring these and other details of TCR‐peptide/MHC binding interactions, but also addressing questions about how TCR binding geometry relates to T cell function, as well as modeling structural properties of class I and class II TCR‐peptide/MHC complexes from sequence information. The system is available at https://tcr3d.ibbr.umd.edu/tcr_com or for download as a script.