Structural basis for the ligand recognition and G protein subtype selectivity of kisspeptin receptor.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 39151001.
- Also identified by DOI 10.1126/sciadv.adn7771 and PMC identifier 11328905.
- Licence recorded as CC BY-NC.
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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 G<sub>i/o</sub> pathway besides the well-known G<sub>q/11</sub> pathway. We further resolved the cryo-electron microscopy (cryo-EM) structure of KISS1R-G<sub>q</sub> and KISS1R-G<sub>i</sub> complexes bound to the synthetic agonist TAK448 and structure of KISS1R-G<sub>q</sub> 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.
Medical subject headings
- Receptors, Kisspeptin-1
- Cryoelectron Microscopy