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- PDB-8i2g: FSHR-Follicle stimulating hormone-compound 716340-Gs complex -

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Basic information

Entry
Database: PDB / ID: 8i2g
TitleFSHR-Follicle stimulating hormone-compound 716340-Gs complex
Components
  • (Guanine nucleotide-binding protein ...) x 2
  • Follicle-stimulating hormone receptor
  • Follitropin subunit beta
  • Glycoprotein hormones alpha chain
  • Nb35
  • chimera of Guanine nucleotide-binding protein G(s) subunit alpha and Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas
KeywordsHORMONE / Follicle stimulating hormone / FSH / GPCR / Gs-protein
Function / homology
Function and homology information


follicle-stimulating hormone receptor activity / regulation of platelet-derived growth factor receptor signaling pathway / regulation of acetylcholine metabolic process / progesterone biosynthetic process / regulation of protein kinase A signaling / regulation of hormone metabolic process / positive regulation of steroid biosynthetic process / follicle-stimulating hormone activity / follicle-stimulating hormone complex / pituitary gonadotropin complex ...follicle-stimulating hormone receptor activity / regulation of platelet-derived growth factor receptor signaling pathway / regulation of acetylcholine metabolic process / progesterone biosynthetic process / regulation of protein kinase A signaling / regulation of hormone metabolic process / positive regulation of steroid biosynthetic process / follicle-stimulating hormone activity / follicle-stimulating hormone complex / pituitary gonadotropin complex / luteinizing hormone secretion / follicle-stimulating hormone secretion / Thyroxine biosynthesis / Mineralocorticoid biosynthesis / adenylate cyclase-activating serotonin receptor signaling pathway / primary ovarian follicle growth / Glycoprotein hormones / Reactions specific to the complex N-glycan synthesis pathway / Hormone ligand-binding receptors / Androgen biosynthesis / follicle-stimulating hormone signaling pathway / female gamete generation / Sertoli cell proliferation / gonad development / intracellular water homeostasis / sperm DNA condensation / negative regulation of organ growth / sensory perception of chemical stimulus / Sertoli cell development / basement membrane organization / transcytosis / regulation of osteoclast differentiation / cellular response to follicle-stimulating hormone stimulus / regulation of systemic arterial blood pressure / female gonad development / mu-type opioid receptor binding / regulation of signaling receptor activity / corticotropin-releasing hormone receptor 1 binding / thyroid hormone generation / G protein-coupled peptide receptor activity / beta-2 adrenergic receptor binding / negative regulation of bone resorption / organ growth / positive regulation of intracellular estrogen receptor signaling pathway / regulation of chromosome organization / uterus development / peptide hormone binding / thyroid gland development / positive regulation of bone resorption / PKA activation in glucagon signalling / developmental growth / D1 dopamine receptor binding / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / response to prostaglandin E / hormone-mediated signaling pathway / adenylate cyclase regulator activity / insulin-like growth factor receptor binding / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / ionotropic glutamate receptor binding / transforming growth factor beta receptor signaling pathway / adenylate cyclase activator activity / locomotory behavior / female pregnancy / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / hormone activity / bone development / G-protein beta/gamma-subunit complex binding / platelet aggregation / Golgi lumen / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / male gonad development / G beta:gamma signalling through BTK / neuron projection development / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding
Similarity search - Function
Follicle stimulating hormone receptor / Gonadotropin hormone receptor, transmembrane domain / Gonadotropin hormone receptor transmembrane region / Gonadotropin, beta subunit, conserved site / Glycoprotein hormones beta chain signature 1. / Glycoprotein hormones beta chain signature 2. / Glycoprotein hormone beta chain homologues. / Glycoprotein hormone alpha chain / Glycoprotein hormone / Glycoprotein hormones alpha chain signature 1. ...Follicle stimulating hormone receptor / Gonadotropin hormone receptor, transmembrane domain / Gonadotropin hormone receptor transmembrane region / Gonadotropin, beta subunit, conserved site / Glycoprotein hormones beta chain signature 1. / Glycoprotein hormones beta chain signature 2. / Glycoprotein hormone beta chain homologues. / Glycoprotein hormone alpha chain / Glycoprotein hormone / Glycoprotein hormones alpha chain signature 1. / Glycoprotein hormones alpha chain signature 2. / Glycoprotein hormones alpha chain family profile. / Glycoprotein hormone alpha chain homologues. / Gonadotropin, beta subunit / Glycoprotein hormone subunit beta / Cystine-knot domain / BspA type Leucine rich repeat region / BspA type Leucine rich repeat region (6 copies) / Glycoprotein hormone receptor family / Leucine rich repeat N-terminal domain / Leucine-rich repeat N-terminal domain / Leucine rich repeat N-terminal domain / Cystine-knot cytokine / G-protein alpha subunit, group S / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / Leucine-rich repeat domain superfamily / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / 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) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Immunoglobulins / Immunoglobulin-like / Sandwich / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
CHOLESTEROL / MYRISTIC ACID / Chem-O6F / PALMITIC ACID / Glycoprotein hormones alpha chain / Follitropin subunit beta / Follicle-stimulating hormone receptor / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas / Guanine nucleotide-binding protein G(s) subunit alpha
Similarity search - Component
Biological speciesCricetulus griseus (Chinese hamster)
Homo sapiens (human)
Lama glama (llama)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 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 29, 2023Provider: repository / Type: Initial release
Revision 1.1Apr 5, 2023Group: Source and taxonomy / Structure summary / Category: entity / entity_name_com / entity_src_gen
Item: _entity.pdbx_description / _entity_name_com.name ..._entity.pdbx_description / _entity_name_com.name / _entity_src_gen.gene_src_common_name / _entity_src_gen.pdbx_gene_src_scientific_name
Revision 1.2Nov 20, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: chimera of Guanine nucleotide-binding protein G(s) subunit alpha and Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
N: Nb35
R: Follicle-stimulating hormone receptor
X: Glycoprotein hormones alpha chain
Y: Follitropin subunit beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)196,96931
Polymers188,9407
Non-polymers8,02924
Water00
1


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

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Components

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Protein , 4 types, 4 molecules ARXY

#1: Protein chimera of Guanine nucleotide-binding protein G(s) subunit alpha and Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas / Adenylate cyclase-stimulating G alpha protein / Adenylate cyclase-stimulating G alpha protein / ...Adenylate cyclase-stimulating G alpha protein / Adenylate cyclase-stimulating G alpha protein / Extra large alphas protein / XLalphas


Mass: 30168.227 Da / Num. of mol.: 1 / Mutation: S205T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Cricetulus griseus (Chinese hamster), (gene. exp.) Homo sapiens (human)
Gene: GNAS, GNAS, GNAS1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8R4A8, UniProt: Q5JWF2
#5: Protein Follicle-stimulating hormone receptor / FSH-R / Follitropin receptor


Mass: 76683.680 Da / Num. of mol.: 1 / Mutation: S273I
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
#6: Protein Glycoprotein hormones alpha chain / Anterior pituitary glycoprotein hormones common subunit alpha / Choriogonadotropin alpha chain / ...Anterior pituitary glycoprotein hormones common subunit alpha / Choriogonadotropin alpha chain / Chorionic gonadotrophin subunit alpha / CG-alpha / Follicle-stimulating hormone alpha chain / FSH-alpha / Follitropin alpha chain / Luteinizing hormone alpha chain / LSH-alpha / Lutropin alpha chain / Thyroid-stimulating hormone alpha chain / TSH-alpha / Thyrotropin alpha chain


Mass: 10183.753 Da / Num. of mol.: 1 / Mutation: F17L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CGA / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P01215
#7: Protein Follitropin subunit beta / Follicle-stimulating hormone beta subunit / FSH-B / FSH-beta / Follitropin beta chain


Mass: 12241.914 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FSHB / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P01225

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Guanine nucleotide-binding protein ... , 2 types, 2 molecules BG

#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37915.496 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Antibody , 1 types, 1 molecules N

#4: Antibody Nb35


Mass: 13885.439 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)

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Sugars , 2 types, 5 molecules

#8: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#12: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 4 types, 19 molecules

#9: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: C27H46O
#10: Chemical ChemComp-PLM / PALMITIC ACID


Mass: 256.424 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C16H32O2
#11: Chemical ChemComp-MYR / MYRISTIC ACID


Mass: 228.371 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H28O2
#13: Chemical 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


Mass: 467.624 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H33N3O3S / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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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: FSHR-Follicle stimulating hormone-compound 716340-Gs complex
Type: COMPLEX / Entity ID: #1-#7 / 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: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 477950 / Symmetry type: POINT

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