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- PDB-8i2h: Follicle stimulating hormone receptor -

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Basic information

Entry
Database: PDB / ID: 8i2h
TitleFollicle stimulating hormone receptor
ComponentsFollicle-stimulating hormone receptor
KeywordsHORMONE / FSH / FSHR / GPCR
Function / homology
Function and homology information


follicle-stimulating hormone receptor activity / Hormone ligand-binding receptors / follicle-stimulating hormone signaling pathway / female gamete generation / gonad development / cellular response to follicle-stimulating hormone stimulus / regulation of protein kinase A signaling / G protein-coupled peptide receptor activity / female gonad development / hormone-mediated signaling pathway ...follicle-stimulating hormone receptor activity / Hormone ligand-binding receptors / follicle-stimulating hormone signaling pathway / female gamete generation / gonad development / cellular response to follicle-stimulating hormone stimulus / regulation of protein kinase A signaling / G protein-coupled peptide receptor activity / female gonad development / hormone-mediated signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / male gonad development / G alpha (s) signalling events / spermatogenesis / positive regulation of ERK1 and ERK2 cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / G protein-coupled receptor signaling pathway / membrane / plasma membrane
Similarity search - Function
Follicle stimulating hormone receptor / Gonadotropin hormone receptor, transmembrane domain / Gonadotropin hormone receptor transmembrane region / BspA type Leucine rich repeat region / Glycoprotein hormone receptor family / BspA type Leucine rich repeat region (6 copies) / Leucine rich repeat N-terminal domain / Leucine-rich repeat N-terminal domain / Leucine rich repeat N-terminal domain / Leucine-rich repeat domain superfamily ...Follicle stimulating hormone receptor / Gonadotropin hormone receptor, transmembrane domain / Gonadotropin hormone receptor transmembrane region / BspA type Leucine rich repeat region / Glycoprotein hormone receptor family / BspA type Leucine rich repeat region (6 copies) / Leucine rich repeat N-terminal domain / Leucine-rich repeat N-terminal domain / Leucine rich repeat N-terminal domain / Leucine-rich repeat domain superfamily / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family)
Similarity search - Domain/homology
Follicle-stimulating hormone receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 6 Å
AuthorsDuan, J. / Xu, P. / Yang, J. / Ji, Y. / Zhang, H. / Mao, C. / Luan, X. / Jiang, Y. / Zhang, Y. / Zhang, S. / Xu, H.E.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32130022 China
CitationJournal: Nat Commun / Year: 2023
Title: Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor.
Authors: Jia 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 /
Abstract: 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 ...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.
History
DepositionJan 14, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 22, 2023Provider: repository / Type: Initial release
Revision 1.1Jul 3, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Follicle-stimulating hormone receptor


Theoretical massNumber of molelcules
Total (without water)76,9721
Polymers76,9721
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Follicle-stimulating hormone receptor / FSH-R / Follitropin receptor


Mass: 76971.930 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FSHR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P23945

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Follicle stimulating hormone receptor / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: OTHER / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 70 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 356211 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0012888
ELECTRON MICROSCOPYf_angle_d0.394047
ELECTRON MICROSCOPYf_dihedral_angle_d2.129566
ELECTRON MICROSCOPYf_chiral_restr0.043549
ELECTRON MICROSCOPYf_plane_restr0.003589

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