Kobilka Institute of Innovative Drug Discovery, Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, 518172 Shenzhen, Guangdong, China.
The Huanan Affiliated Hospital of Shenzhen University, Shenzhen University, 518000 Shenzhen, Guangdong, China.
Sci Adv. 2024 Aug 16;10(33):eadn7771. doi: 10.1126/sciadv.adn7771.
Kisspeptin receptor (KISS1R), belonging to the class A peptide-GPCR family, plays a key role in the regulation of reproductive physiology after stimulation by kisspeptin and is regarded as an attractive drug target for reproductive diseases. Here, we demonstrated that KISS1R can couple to the G pathway besides the well-known G pathway. We further resolved the cryo-electron microscopy (cryo-EM) structure of KISS1R-G and KISS1R-G complexes bound to the synthetic agonist TAK448 and structure of KISS1R-G complex bound to the endogenous agonist KP54. The high-resolution structures provided clear insights into mechanism of KISS1R recognition by its ligand and can facilitate the design of targeted drugs with high affinity to improve treatment effects. Moreover, the structural and functional analyses indicated that conformational differences in the extracellular loops (ECLs), intracellular loops (ICLs) of the receptor, and the "wavy hook" of the Gα subunit may account for the specificity of G protein coupling for KISS1R signaling.
Kisspeptin 受体（KISS1R）属于 A 类肽 GPCR 家族，在受到 kisspeptin 刺激后，在生殖生理调节中发挥关键作用，被认为是生殖疾病有吸引力的药物靶点。在这里，我们证明了 KISS1R 除了众所周知的 G 途径外，还可以与 G 途径偶联。我们进一步解析了 KISS1R-G 和与合成激动剂 TAK448 结合的 KISS1R-G 复合物的冷冻电镜（cryo-EM）结构，以及与内源性激动剂 KP54 结合的 KISS1R-G 复合物的结构。高分辨率结构提供了对 KISS1R 与其配体识别机制的清晰认识，并有助于设计具有高亲和力的靶向药物，以提高治疗效果。此外，结构和功能分析表明，受体的细胞外环（ECL）、细胞内环（ICL）和 Gα 亚基的“波浪钩”的构象差异可能是 KISS1R 信号转导中 G 蛋白偶联特异性的原因。
