iHuman Institute, ShanghaiTech University, Shanghai, China.
School of Life Science and Technology, Shanghai Key Laboratory of High-resolution Electron Microscopy, ShanghaiTech University, Shanghai, China.
Nat Commun. 2024 Jun 19;15(1):5255. doi: 10.1038/s41467-024-49625-y.
GPRC5D is an atypical Class C orphan G protein-coupled receptor. Its high expression on the surface of multiple myeloma cells has rendered it an attractive target for therapeutic interventions, including monoclonal antibodies, CAR-T cells, and T-cell engagers. Despite its therapeutic potential, the insufficient understanding regarding of the receptor's structure and antibody recognition mechanism has impeded the progress of effective therapeutic development. Here, we present the structure of GPRC5D in complex with a preclinical-stage single-chain antibody (scFv). Our structural analysis reveals that the GPRC5D presents a close resemblance to the typical Class C GPCRs in the transmembrane region. We identify a distinct head-to-head homodimer arrangement and interface mainly involving TM4, setting it apart from other Class C homo- or hetero-dimers. Furthermore, we elucidate the binding site engaging a sizable extracellular domain on GPRC5D for scFv recognition. These insights not only unveil the distinctive dimer organization of this unconventional Class C GPCR but also hold the potential to advance drug development targeting GPRC5D for the treatment of multiple myeloma.
GPRC5D 是一种非典型的 C 类孤儿 G 蛋白偶联受体。其在多发性骨髓瘤细胞表面的高表达使其成为治疗干预的一个有吸引力的靶点，包括单克隆抗体、CAR-T 细胞和 T 细胞衔接子。尽管具有治疗潜力，但由于对该受体结构和抗体识别机制的了解不足，阻碍了有效治疗方法的开发进展。在这里，我们展示了 GPRC5D 与一种临床前阶段的单链抗体（scFv）复合物的结构。我们的结构分析表明，GPRC5D 在跨膜区域与典型的 C 类 GPCR 具有非常相似的结构。我们确定了一种独特的头对头同源二聚体排列和主要涉及 TM4 的界面，使其与其他 C 类同型或异型二聚体区分开来。此外，我们阐明了与 GPRC5D 上相当大的细胞外结构域结合的 scFv 识别结合位点。这些见解不仅揭示了这种非典型 C 类 GPCR 的独特二聚体组织，而且有可能推进针对多发性骨髓瘤的 GPRC5D 药物开发。
