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Yorodumi- EMDB-25763: M22 Agonist Autoantibody bound to Human Thyrotropin receptor in c... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-25763 | |||||||||
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Title | M22 Agonist Autoantibody bound to Human Thyrotropin receptor in complex with miniGs399 (composite structure) | |||||||||
Map data | Sharpened composite map | |||||||||
Sample |
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Function / homology | Function and homology information thyroid-stimulating hormone receptor activity / cochlea morphogenesis / inner ear receptor cell stereocilium organization / positive regulation of multicellular organism growth / dopaminergic neuron differentiation / G protein-coupled peptide receptor activity / regulation of locomotion / PKA activation in glucagon signalling / hair follicle placode formation / lateral plasma membrane ...thyroid-stimulating hormone receptor activity / cochlea morphogenesis / inner ear receptor cell stereocilium organization / positive regulation of multicellular organism growth / dopaminergic neuron differentiation / G protein-coupled peptide receptor activity / regulation of locomotion / PKA activation in glucagon signalling / hair follicle placode formation / lateral plasma membrane / mu-type opioid receptor binding / developmental growth / corticotropin-releasing hormone receptor 1 binding / intracellular transport / D1 dopamine receptor binding / Hedgehog 'off' state / beta-2 adrenergic receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / adenylate cyclase activator activity / hormone-mediated signaling pathway / adult locomotory behavior / B cell differentiation / trans-Golgi network membrane / insulin-like growth factor receptor binding / ionotropic glutamate receptor binding / G-protein beta/gamma-subunit complex binding / bone development / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / cognition / 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 / platelet aggregation / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / 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 / sensory perception of smell / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / positive regulation of cold-induced thermogenesis / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / basolateral plasma membrane / cell population proliferation / Ras protein signal transduction / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / GTP binding / signal transduction / extracellular exosome / membrane / metal ion binding / plasma membrane / cytoplasm / cytosol Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.9 Å | |||||||||
Authors | Faust B / Cheng Y / Manglik A | |||||||||
Funding support | 2 items
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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
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_25763.map.gz | 256.9 MB | EMDB map data format | |
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Header (meta data) | emd-25763-v30.xml emd-25763.xml | 22.2 KB 22.2 KB | Display Display | EMDB header |
Images | emd_25763.png | 110.4 KB | ||
Others | emd_25763_additional_1.map.gz | 130.7 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-25763 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-25763 | HTTPS FTP |
-Validation report
Summary document | emd_25763_validation.pdf.gz | 446.7 KB | Display | EMDB validaton report |
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Full document | emd_25763_full_validation.pdf.gz | 446.3 KB | Display | |
Data in XML | emd_25763_validation.xml.gz | 7.2 KB | Display | |
Data in CIF | emd_25763_validation.cif.gz | 8.2 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-25763 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-25763 | HTTPS FTP |
-Related structure data
Related structure data | 7t9nMC 7t9iC 7t9mC 7utzC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_25763.map.gz / Format: CCP4 / Size: 278.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Annotation | Sharpened composite map | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.844 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Additional map: Unsharpened composite map
File | emd_25763_additional_1.map | ||||||||||||
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Annotation | Unsharpened composite map | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
+Entire : M22 agonist autoantibody bound to human Thyrotropin receptor in c...
+Supramolecule #1: M22 agonist autoantibody bound to human Thyrotropin receptor in c...
+Macromolecule #1: M22 Fab light chain
+Macromolecule #2: M22 Fab heavy chain
+Macromolecule #3: Nanobody 35
+Macromolecule #4: Thyrotropin receptor
+Macromolecule #5: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
+Macromolecule #6: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Macromolecule #7: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Macromolecule #8: (2S)-3-hydroxypropane-1,2-diyl dihexadecanoate
+Macromolecule #9: 2-acetamido-2-deoxy-beta-D-glucopyranose
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | TFS KRIOS |
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Specialist optics | Energy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 81000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
+Image processing
-Atomic model buiding 1
Refinement | Protocol: FLEXIBLE FIT |
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Output model | PDB-7t9n: |