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TitleStructural basis for hormone recognition and distinctive Gq protein coupling by the kisspeptin receptor.
Journal, issue, pagesCell Rep, Vol. 43, Issue 7, Page 114389, Year 2024
Publish dateJul 23, 2024
AuthorsShiyi Shen / Dongxue Wang / Heng Liu / Xinheng He / Yinglong Cao / Juanhua Chen / Shujie Li / Xi Cheng / H Eric Xu / Jia Duan /
PubMed AbstractKisspeptin 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 ...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 G-coupled receptors, enabling distinct interactions with G. This study reveals the molecular intricacies governing ligand binding and activation of KISS1R, while highlighting its exceptional ability to couple with G. Our findings pave the way for structure-guided design of therapeutics targeting this physiologically indispensable receptor.
External linksCell Rep / PubMed:38935498
MethodsEM (single particle)
Resolution3.06 - 3.07 Å
Structure data

60141

8zjd

EMDB-60141, PDB-8zjd:
Cryo-EM structure of kisspeptin receptor bound to KP-10
Method: EM (single particle) / Resolution: 3.06 Å

60142

8zje

EMDB-60142, PDB-8zje:
Cryo-EM structure of kisspeptin receptor bound to TAK-448
Method: EM (single particle) / Resolution: 3.07 Å

Source
  • homo sapiens (human)
  • synthetic construct (others)
  • mus sp. (mice)
KeywordsMEMBRANE PROTEIN / Cryo-EM / kisspeptin receptor / GPR54 / KISS1R / G proteins

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