9E6Y
Structure of CD112 (Nectin-2) domain 1 bound to CD112R (PVRIG)
Summary for 9E6Y
| Entry DOI | 10.2210/pdb9e6y/pdb |
| Related | 4DFH |
| Descriptor | Nectin-2, Transmembrane protein PVRIG, 1,2-ETHANEDIOL, ... (5 entities in total) |
| Functional Keywords | checkpoint receptor immunoglobulin folding, immunosuppressant |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 29245.95 |
| Authors | |
| Primary citation | Singh, S.,Julia, E.,Kalita, P.,Mason, C.,Ming, Q.,Lee-Sam, A.,Gordon, S.,Buitrago, M.E.,Leung, D.W.,Hwu, P.,Luca, V.C. Structure-guided engineering of CD112 receptor variants for optimized immunotherapy. Mol.Ther., 2025 Cited by PubMed Abstract: The immune checkpoint protein, CD112 receptor (CD112R, also known as PVRIG), suppresses T and NK cell activation upon binding to tumor-expressed CD112 (Nectin-2) ligands. Here, we determine the structure of the CD112-CD112R complex and use it to guide the engineering of multiple CD112-targeting immunotherapy candidates. The 2.2 Å-resolution crystal structure reveals an antiparallel, lock-and-key binding mode in which CD112R disrupts CD112 homodimerization. Structural analysis informed directed evolution campaigns focused on remodeling the CD112-CD112R interface, resulting in the isolation of CD112R mutants with greatly increased expression and CD112-binding affinity. The highest-affinity variant, CD112R, potently inhibits CD112-CD112R interactions when utilized as a soluble CD112 trap. Furthermore, incorporating CD112R variants into chimeric antigen receptors (CARs) and T cell engagers (TCEs) leads to more robust T cell activation and killing of CD112 triple-negative breast cancer (TNBC) cells compared to wild-type CD112R. This strategy demonstrates how structural insights can be leveraged to efficiently generate panels of "affinity-tuned" biologics for immunotherapy. PubMed: 40285356DOI: 10.1016/j.ymthe.2025.04.032 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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