9e6y
Structure of CD112 (Nectin-2) domain 1 bound to CD112R (PVRIG)
Structural highlights
FunctionPVRIG_HUMAN Cell surface receptor for NECTIN2. May act as a coinhibitory receptor that suppresses T-cell receptor-mediated signals. Following interaction with NECTIN2, inhibits T-cell proliferation. Competes with CD226 for NECTIN2-binding.[1] Publication Abstract from PubMedThe 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 A-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(IVE), 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. Structure-guided engineering of CD112 receptor variants for optimized immunotherapy.,Singh S, Julia E, Kalita P, Mason C, Ming Q, Lee-Sam A, Gordon S, Buitrago ME, Leung DW, Hwu P, Luca VC Mol Ther. 2025 Apr 24:S1525-0016(25)00311-9. doi: 10.1016/j.ymthe.2025.04.032. PMID:40285356[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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