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

Luca, V.C.,Singh, S. (deposition date: 2024-10-31, release date: 2025-05-07, Last modification date: 2025-08-20)

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., 33:3590-3604, 2025

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: 40285356
DOI: 10.1016/j.ymthe.2025.04.032

Experimental method

X-RAY DIFFRACTION (2.2 Å)