Structural basis for hormone recognition and distinctive Gq protein coupling by the kisspeptin receptor.
Cell Rep
; 43(7): 114389, 2024 Jul 23.
Article
in En
| MEDLINE
| ID: mdl-38935498
ABSTRACT
Kisspeptin signaling through its G protein-coupled receptor, KISS1R, plays an indispensable role in regulating reproduction via the hypothalamic-pituitary-gonadal axis. Dysregulation of this pathway underlies severe disorders like infertility and precocious puberty. Here, we present cryo-EM structures of KISS1R bound to the endogenous agonist kisspeptin-10 and a synthetic analog TAK-448. These structures reveal pivotal interactions between peptide ligands and KISS1R extracellular loops for receptor activation. Both peptides exhibit a conserved binding mode, unveiling their common activation mechanism. Intriguingly, KISS1R displays a distinct 40° angular deviation in its intracellular TM6 region compared to other Gq-coupled receptors, enabling distinct interactions with Gq. This study reveals the molecular intricacies governing ligand binding and activation of KISS1R, while highlighting its exceptional ability to couple with Gq. Our findings pave the way for structure-guided design of therapeutics targeting this physiologically indispensable receptor.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
GTP-Binding Protein alpha Subunits, Gq-G11
/
Kisspeptins
/
Receptors, Kisspeptin-1
Limits:
Humans
Language:
En
Journal:
Cell Rep
Year:
2024
Document type:
Article
Affiliation country: