8xgu
a peptide receptor complex structure
Structural highlights
DiseaseKISSR_HUMAN Genetic central precocious puberty in male;Genetic central precocious puberty in female;Normosmic congenital hypogonadotropic hypogonadism. The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in KISS1R as well as in other HH-associated genes including FGFR1 and IL17RD (PubMed:23643382).[1] The disease is caused by variants affecting the gene represented in this entry. FunctionKISSR_HUMAN Receptor for metastin (kisspeptin-54 or kp-54), a C-terminally amidated peptide of KiSS1. KiSS1 is a metastasis suppressor protein that suppresses metastases in malignant melanomas and in some breast carcinomas without affecting tumorigenicity. The metastasis suppressor properties may be mediated in part by cell cycle arrest and induction of apoptosis in malignant cells. The receptor is essential for normal gonadotropin-released hormone physiology and for puberty. The hypothalamic KiSS1/KISS1R system is a pivotal factor in central regulation of the gonadotropic axis at puberty and in adulthood. The receptor is also probably involved in the regulation and fine-tuning of trophoblast invasion generated by the trophoblast itself. Analysis of the transduction pathways activated by the receptor identifies coupling to phospholipase C and intracellular calcium release through pertussis toxin-insensitive G(q) proteins.[2] Publication Abstract from PubMedKisspeptin 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(i/o) pathway besides the well-known G(q/11) pathway. We further resolved the cryo-electron microscopy (cryo-EM) structure of KISS1R-G(q) and KISS1R-G(i) complexes bound to the synthetic agonist TAK448 and structure of KISS1R-G(q) 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 Galpha subunit may account for the specificity of G protein coupling for KISS1R signaling. Structural basis for the ligand recognition and G protein subtype selectivity of kisspeptin receptor.,Wu Z, Chen G, Qiu C, Yan X, Xu L, Jiang S, Xu J, Han R, Shi T, Liu Y, Gao W, Wang Q, Li J, Ye F, Pan X, Zhang Z, Ning P, Zhang B, Chen J, Du Y Sci Adv. 2024 Aug 16;10(33):eadn7771. doi: 10.1126/sciadv.adn7771. Epub 2024 Aug , 16. PMID:39151001[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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