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Yorodumi- PDB-7utz: Human thyrotropin analog TR1402 bound to human Thyrotropin recept... -
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-Basic information
Entry | Database: PDB / ID: 7utz | |||||||||
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Title | Human thyrotropin analog TR1402 bound to human Thyrotropin receptor in complex with miniGs399 (composite structure) | |||||||||
Components |
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Keywords | MEMBRANE PROTEIN / G protein-coupled receptor / Thyroid-stimulating hormone receptor / Thyrotropin receptor / TSH / Thyroid | |||||||||
Function / homology | Function and homology information thyroid-stimulating hormone receptor activity / 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 / Hormone ligand-binding receptors ...thyroid-stimulating hormone receptor activity / 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 / Hormone ligand-binding receptors / Glycoprotein hormones / Reactions specific to the complex N-glycan synthesis pathway / Androgen biosynthesis / follicle-stimulating hormone signaling pathway / cochlea morphogenesis / inner ear receptor cell stereocilium organization / negative regulation of organ growth / positive regulation of multicellular organism growth / thyroid hormone generation / dopaminergic neuron differentiation / response to vitamin A / regulation of signaling receptor activity / regulation of locomotion / organ growth / PKA activation in glucagon signalling / thyroid gland development / hair follicle placode formation / developmental growth / D1 dopamine receptor binding / lateral plasma membrane / anatomical structure morphogenesis / intracellular transport / Hedgehog 'off' state / positive regulation of cAMP-mediated signaling / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / adenylate cyclase activator activity / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / hormone-mediated signaling pathway / adult locomotory behavior / B cell differentiation / trans-Golgi network membrane / Olfactory Signaling Pathway / G-protein beta/gamma-subunit complex binding / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / bone development / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / hormone activity / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / platelet aggregation / cognition / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / positive regulation of GTPase activity / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / Golgi lumen / response to calcium ion / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / response to estrogen / sensory perception of taste / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / sensory perception of smell / Thrombin signalling through proteinase activated receptors (PARs) / cell-cell signaling / retina development in camera-type eye / GTPase binding / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cold-induced thermogenesis / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.4 Å | |||||||||
Authors | Faust, B. / Cheng, Y. / Manglik, A. | |||||||||
Funding support | United States, 2items
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Citation | Journal: Nature / Year: 2022 Title: Autoantibody mimicry of hormone action at the thyrotropin receptor. Authors: Bryan Faust / Christian B Billesbølle / Carl-Mikael Suomivuori / Isha Singh / Kaihua Zhang / Nicholas Hoppe / Antonio F M Pinto / Jolene K Diedrich / Yagmur Muftuoglu / Mariusz W ...Authors: Bryan Faust / Christian B Billesbølle / Carl-Mikael Suomivuori / Isha Singh / Kaihua Zhang / Nicholas Hoppe / Antonio F M Pinto / Jolene K Diedrich / Yagmur Muftuoglu / Mariusz W Szkudlinski / Alan Saghatelian / Ron O Dror / Yifan Cheng / Aashish Manglik / Abstract: Thyroid hormones are vital in metabolism, growth and development. Thyroid hormone synthesis is controlled by thyrotropin (TSH), which acts at the thyrotropin receptor (TSHR). In patients with Graves' ...Thyroid hormones are vital in metabolism, growth and development. Thyroid hormone synthesis is controlled by thyrotropin (TSH), which acts at the thyrotropin receptor (TSHR). In patients with Graves' disease, autoantibodies that activate the TSHR pathologically increase thyroid hormone activity. How autoantibodies mimic thyrotropin function remains unclear. Here we determined cryo-electron microscopy structures of active and inactive TSHR. In inactive TSHR, the extracellular domain lies close to the membrane bilayer. Thyrotropin selects an upright orientation of the extracellular domain owing to steric clashes between a conserved hormone glycan and the membrane bilayer. An activating autoantibody from a patient with Graves' disease selects a similar upright orientation of the extracellular domain. Reorientation of the extracellular domain transduces a conformational change in the seven-transmembrane-segment domain via a conserved hinge domain, a tethered peptide agonist and a phospholipid that binds within the seven-transmembrane-segment domain. Rotation of the TSHR extracellular domain relative to the membrane bilayer is sufficient for receptor activation, revealing a shared mechanism for other glycoprotein hormone receptors that may also extend to other G-protein-coupled receptors with large extracellular domains. | |||||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7utz.cif.gz | 503.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7utz.ent.gz | 414.6 KB | Display | PDB format |
PDBx/mmJSON format | 7utz.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ut/7utz ftp://data.pdbj.org/pub/pdb/validation_reports/ut/7utz | HTTPS FTP |
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-Related structure data
Related structure data | 26795MC 7t9iC 7t9mC 7t9nC 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 , 3 types, 3 molecules ABR
#1: Protein | Mass: 10364.058 Da / Num. of mol.: 1 / Mutation: Q13R, E14R, P16R, Q20R Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: CGA / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P01215 |
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#2: Protein | Mass: 12915.974 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: TSHB / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P01222 |
#4: Protein | Mass: 79641.273 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: TSHR / Production host: Homo sapiens (human) / References: UniProt: A0A0A0MTJ0 |
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules XYZ
#5: Protein | Mass: 30137.025 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Production host: Homo sapiens (human) / References: UniProt: P63092 |
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#6: Protein | Mass: 40786.566 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Homo sapiens (human) / References: UniProt: P62873 |
#7: 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: Homo sapiens (human) / References: UniProt: P59768 |
-Antibody / Sugars / Non-polymers , 3 types, 9 molecules N
#3: Antibody | Mass: 15398.067 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) | ||
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#8: Sugar | ChemComp-NAG / #9: Chemical | ChemComp-Z41 / ( | |
-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: Human TSH analog TR1402 bound to human Thyrotropin receptor in complex with miniGs399 (composite structure) Type: COMPLEX / Entity ID: #1-#7 / Source: RECOMBINANT |
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Molecular weight | Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) / Strain: expi293 |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: TFS KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 105000 X / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
EM imaging optics | Energyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV |
-Processing
Software | Name: PHENIX / Version: 1.19.1_4122: / Classification: refinement | ||||||||||||||||||||||||||||||||
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 7940651 | ||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 2.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 375930 Details: 2.4A GS-FSC refers to Thyrotropin receptor transmembrane domain in complex with heterotrimeric G proteins. Extracellular domain in complex with TR1402 TSH analog GS-FSC is 2.7A. Symmetry type: POINT | ||||||||||||||||||||||||||||||||
Atomic model building | Protocol: FLEXIBLE FIT | ||||||||||||||||||||||||||||||||
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