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- EMDB-26795: Human thyrotropin analog TR1402 bound to human Thyrotropin recept... -
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Open data
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Basic information
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Title | Human thyrotropin analog TR1402 bound to human Thyrotropin receptor in complex with miniGs399 (composite structure) | |||||||||
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Function / homology | ![]() 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 / thyroid hormone generation / dopaminergic neuron differentiation / positive regulation of multicellular organism growth / regulation of signaling receptor activity / response to vitamin A / regulation of locomotion / organ growth / PKA activation in glucagon signalling / thyroid gland development / hair follicle placode formation / lateral plasma membrane / developmental growth / D1 dopamine receptor binding / intracellular transport / anatomical structure morphogenesis / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / hormone-mediated signaling pathway / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / adenylate cyclase activator activity / B cell differentiation / adult locomotory behavior / trans-Golgi network membrane / response to calcium ion / 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-coupled acetylcholine receptor signaling pathway / hormone activity / G-protein activation / 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 / platelet aggregation / 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 / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Golgi lumen / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / response to estrogen / 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 / cell-cell signaling / retina development in camera-type eye / Ca2+ pathway / positive regulation of cold-induced thermogenesis / phospholipase C-activating G protein-coupled receptor signaling pathway / basolateral plasma membrane / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / Ras protein signal transduction Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.4 Å | |||||||||
![]() | Faust B / Cheng Y / Manglik A | |||||||||
Funding support | ![]()
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![]() | ![]() 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. | |||||||||
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Structure visualization
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Downloads & links
-EMDB archive
Map data | ![]() | 243.6 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 22.6 KB 22.6 KB | Display Display | ![]() |
Images | ![]() | 88.7 KB | ||
Others | ![]() | 131.7 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7utzMC ![]() 7t9iC ![]() 7t9mC ![]() 7t9nC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | Sharpened composite map | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.831 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_26795_additional_1.map | ||||||||||||
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Annotation | Unsharpened composite map | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
+Entire : Human TSH analog TR1402 bound to human Thyrotropin receptor in co...
+Supramolecule #1: Human TSH analog TR1402 bound to human Thyrotropin receptor in co...
+Macromolecule #1: Glycoprotein hormones alpha chain analog TR1402
+Macromolecule #2: Thyrotropin subunit beta
+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: 2-acetamido-2-deoxy-beta-D-glucopyranose
+Macromolecule #9: (2S)-3-hydroxypropane-1,2-diyl dihexadecanoate
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV |
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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: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 105000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
-Atomic model buiding 1
Refinement | Protocol: FLEXIBLE FIT |
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Output model | ![]() PDB-7utz: |