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TitleMechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 519, Year 2023
Publish dateJan 31, 2023
AuthorsJia Duan / Peiyu Xu / Huibing Zhang / Xiaodong Luan / Jiaqi Yang / Xinheng He / Chunyou Mao / Dan-Dan Shen / Yujie Ji / Xi Cheng / Hualiang Jiang / Yi Jiang / Shuyang Zhang / Yan Zhang / H Eric Xu /
PubMed AbstractFollicle stimulating hormone (FSH) is an essential glycoprotein hormone for human reproduction, which functions are mediated by a G protein-coupled receptor, FSHR. Aberrant FSH-FSHR signaling causes ...Follicle stimulating hormone (FSH) is an essential glycoprotein hormone for human reproduction, which functions are mediated by a G protein-coupled receptor, FSHR. Aberrant FSH-FSHR signaling causes infertility and ovarian hyperstimulation syndrome. Here we report cryo-EM structures of FSHR in both inactive and active states, with the active structure bound to FSH and an allosteric agonist compound 21 f. The structures of FSHR are similar to other glycoprotein hormone receptors, highlighting a conserved activation mechanism of hormone-induced receptor activation. Compound 21 f formed extensive interactions with the TMD to directly activate FSHR. Importantly, the unique residue H615 in FSHR plays an essential role in determining FSHR selectivity for various allosteric agonists. Together, our structures provide a molecular basis of FSH and small allosteric agonist-mediated FSHR activation, which could inspire the design of FSHR-targeted drugs for the treatment of infertility and controlled ovarian stimulation for in vitro fertilization.
External linksNat Commun / PubMed:36720854 / PubMed Central
MethodsEM (single particle)
Resolution2.8 - 6.0 Å
Structure data

35135

8i2g

EMDB-35135, PDB-8i2g:
FSHR-Follicle stimulating hormone-compound 716340-Gs complex
Method: EM (single particle) / Resolution: 2.8 Å

35136

8i2h

EMDB-35136, PDB-8i2h:
Follicle stimulating hormone receptor
Method: EM (single particle) / Resolution: 6.0 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL

ChemComp-PLM:
PALMITIC ACID

ChemComp-MYR:
MYRISTIC ACID

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-O6F:
N-tert-butyl-N-ethyl-8-methoxy-9-propan-2-yloxy-1-thiophen-2-yl-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carboxamide

Source
  • homo sapiens (human)
  • lama glama (llama)
  • cricetulus griseus (Chinese hamster)
KeywordsHORMONE / Follicle stimulating hormone / FSH / GPCR / Gs-protein / FSHR

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