+Open data
-Basic information
Entry | Database: PDB / ID: 8i2g | ||||||
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Title | FSHR-Follicle stimulating hormone-compound 716340-Gs complex | ||||||
Components |
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Keywords | HORMONE / Follicle stimulating hormone / FSH / GPCR / Gs-protein | ||||||
Function / homology | Function and homology information follicle-stimulating hormone receptor activity / progesterone biosynthetic process / follicle-stimulating hormone activity / follicle-stimulating hormone complex / pituitary gonadotropin complex / luteinizing hormone secretion / follicle-stimulating hormone secretion / positive regulation of steroid biosynthetic process / Thyroxine biosynthesis / Mineralocorticoid biosynthesis ...follicle-stimulating hormone receptor activity / progesterone biosynthetic process / follicle-stimulating hormone activity / follicle-stimulating hormone complex / pituitary gonadotropin complex / luteinizing hormone secretion / follicle-stimulating hormone secretion / positive regulation of steroid biosynthetic process / Thyroxine biosynthesis / Mineralocorticoid biosynthesis / Glycoprotein hormones / Hormone ligand-binding receptors / Reactions specific to the complex N-glycan synthesis pathway / Androgen biosynthesis / follicle-stimulating hormone signaling pathway / female gamete generation / Sertoli cell proliferation / gonad development / PKA activation in glucagon signalling / sensory perception of chemical stimulus / positive regulation of cAMP-mediated signaling / negative regulation of organ growth / regulation of osteoclast differentiation / cellular response to follicle-stimulating hormone stimulus / mu-type opioid receptor binding / developmental growth / corticotropin-releasing hormone receptor 1 binding / regulation of protein kinase A signaling / D1 dopamine receptor binding / thyroid hormone generation / G protein-coupled peptide receptor activity / regulation of signaling receptor activity / Hedgehog 'off' state / beta-2 adrenergic receptor binding / organ growth / female gonad development / adenylate cyclase-activating adrenergic receptor signaling pathway / adenylate cyclase activator activity / thyroid gland development / positive regulation of bone resorption / insulin-like growth factor receptor binding / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / hormone-mediated signaling pathway / ionotropic glutamate receptor binding / bone development / G-protein beta/gamma-subunit complex binding / transforming growth factor beta receptor signaling pathway / positive regulation of GTPase activity / platelet aggregation / female pregnancy / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / hormone activity / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Glucagon signaling in metabolic regulation / 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 / G beta:gamma signalling through CDC42 / Vasopressin regulates renal water homeostasis via Aquaporins / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / G alpha (z) signalling events / Golgi lumen / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / male gonad development / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / GPER1 signaling / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / G alpha (12/13) signalling events / extracellular vesicle / positive regulation of cold-induced thermogenesis / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / fibroblast proliferation Similarity search - Function | ||||||
Biological species | Cricetulus griseus (Chinese hamster) Homo sapiens (human) Lama glama (llama) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å | ||||||
Authors | Duan, 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
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8i2g.cif.gz | 649.1 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8i2g.ent.gz | 548.9 KB | Display | PDB format |
PDBx/mmJSON format | 8i2g.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8i2g_validation.pdf.gz | 1.6 MB | Display | wwPDB validaton report |
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Full document | 8i2g_full_validation.pdf.gz | 1.6 MB | Display | |
Data in XML | 8i2g_validation.xml.gz | 54.5 KB | Display | |
Data in CIF | 8i2g_validation.cif.gz | 79.2 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/i2/8i2g ftp://data.pdbj.org/pub/pdb/validation_reports/i2/8i2g | HTTPS FTP |
-Related structure data
Related structure data | 35135MC 8i2hC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 4 types, 4 molecules ARXY
#1: Protein | 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 |
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#5: Protein | 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 | 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 | 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 |
-Guanine nucleotide-binding protein ... , 2 types, 2 molecules BG
#2: Protein | 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 |
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#3: Protein | 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 |
-Antibody , 1 types, 1 molecules N
#4: Antibody | 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 Source method: isolated from a genetically manipulated source |
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#12: Sugar | ChemComp-NAG / |
-Non-polymers , 4 types, 19 molecules
#9: Chemical | ChemComp-CLR / #10: Chemical | #11: Chemical | #13: Chemical | ChemComp-O6F / | |
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-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: FSHR-Follicle stimulating hormone-compound 716340-Gs complex Type: COMPLEX / Entity ID: #1-#7 / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Spodoptera frugiperda (fall armyworm) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE-PROPANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER |
Electron lens | Mode: OTHER / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) |
-Processing
CTF correction | Type: NONE |
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3D reconstruction | Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 477950 / Symmetry type: POINT |