Nectin and nectin-like (Necl) co-receptor axis, comprised of receptors DNAM-1, TIGIT, CD96, PVRIG, and nectin/Necl ligands, is gaining prominence in immuno-oncology. Within this axis, the inhibitory receptor PVRIG recognizes Nectin-2 with high affinity, but the underlying molecular basis remains unknown. By determining the crystal structure of PVRIG in complex with Nectin-2, we identified a unique CC' loop in PVRIG, which complements the double-lock-and-key binding mode and contributes to its high affinity for Nectin-2. The association of the corresponding charged residues in the F-strands explains the ligand selectivity of PVRIG toward Nectin-2 but not for Necl-5. Moreover, comprehensive comparisons of the binding capacities between co-receptors and ligands provide innovative insights into the intra-axis immunoregulatory mechanism. Taken together, these findings broaden our understanding of immune recognition and regulation mediated by nectin/Necl co-receptors and provide a rationale for the development of immunotherapeutic strategies targeting the nectin/Necl axis.

Nectin 和 Nectin 样 (Necl) 共受体轴由受体 DNAM-1、TIGIT、CD96、PVRIG 和 nectin/Necl 配体组成，在免疫肿瘤学中越来越受到重视。在该轴内，抑制性受体 PVRIG 以高亲和力识别 Nectin-2，但潜在的分子基础仍然未知。通过确定 PVRIG 与 Nectin-2 复合物的晶体结构，我们在 PVRIG 中发现了一个独特的 CC' 环，它补充了双锁键结合模式，并有助于其与 Nectin-2 的高亲和力。 F 链中相应带电残基的关联解释了 PVRIG 对 Nectin-2 的配体选择性，但对 Necl-5 没有。此外，共受体和配体之间结合能力的全面比较为轴内免疫调节机制提供了创新的见解。总而言之，这些发现拓宽了我们对 nectin/Necl 共受体介导的免疫识别和调节的理解，并为开发针对 nectin/Necl 轴的免疫治疗策略提供了理论基础。