PDF(Pubmed)
Abstract：
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 Gi/o pathway besides the well-known Gq/11 pathway. We further resolved the cryo-electron microscopy (cryo-EM) structure of KISS1R-Gq and KISS1R-Gi complexes bound to the synthetic agonist TAK448 and structure of KISS1R-Gq 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.
摘要：
Kisspeptin受体(KISS1R),属于A类肽-GPCR家族,在kisspeptin刺激后对生殖生理的调节中起关键作用，被认为是生殖疾病的有吸引力的药物靶标。这里,我们证明，除了众所周知的Gq/11途径外，KISS1R还可以与Gi/o途径偶联。我们进一步解析了与合成激动剂TAK448结合的KISS1R-Gq和KISS1R-Gi复合物的低温电子显微镜（cryo-EM）结构以及与内源性激动剂KP54结合的KISS1R-Gq复合物的结构。高分辨率结构为其配体识别KISS1R的机制提供了清晰的见解，并且可以促进具有高亲和力的靶向药物的设计以提高治疗效果。此外，结构和功能分析表明胞外环(ECLs)的构象差异，受体的胞内环（ICL），Gα亚基的“波浪形钩子”可能解释了G蛋白偶联对KISS1R信号传导的特异性。
