+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-33492 | |||||||||
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Title | TSHR-Gs-M22 antibody-ML109 complex | |||||||||
Map data | ||||||||||
Sample |
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Function / homology | Function and homology information thyroid-stimulating hormone signaling pathway / cellular response to glycoprotein / cellular response to thyrotropin-releasing hormone / thyroid-stimulating hormone receptor activity / Hormone ligand-binding receptors / G protein-coupled peptide receptor activity / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / hormone-mediated signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade ...thyroid-stimulating hormone signaling pathway / cellular response to glycoprotein / cellular response to thyrotropin-releasing hormone / thyroid-stimulating hormone receptor activity / Hormone ligand-binding receptors / G protein-coupled peptide receptor activity / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / hormone-mediated signaling pathway / 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 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / 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 / 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 / sensory perception of taste / GPER1 signaling / G-protein beta-subunit binding / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / G alpha (12/13) signalling events / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / cell-cell signaling / signaling receptor activity / 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 / G alpha (q) signalling events / basolateral plasma membrane / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / receptor complex / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / positive regulation of cell population proliferation / protein-containing complex binding / cell surface / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Mus musculus (house mouse) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.78 Å | |||||||||
Authors | Duan J / Xu P / Luan X / Ji Y / Yuan Q / He X / Ye J / Cheng X / Jiang H / Zhang S ...Duan J / Xu P / Luan X / Ji Y / Yuan Q / He X / Ye J / Cheng X / Jiang H / Zhang S / Jiang Y / Xu HE | |||||||||
Funding support | China, 1 items
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Citation | Journal: Nature / Year: 2022 Title: Hormone- and antibody-mediated activation of the thyrotropin receptor. Authors: Jia Duan / Peiyu Xu / Xiaodong Luan / Yujie Ji / Xinheng He / Ning Song / Qingning Yuan / Ye Jin / Xi Cheng / Hualiang Jiang / Jie Zheng / Shuyang Zhang / Yi Jiang / H Eric Xu / Abstract: Thyroid-stimulating hormone (TSH), through activation of its G-protein-coupled thyrotropin receptor (TSHR), controls the synthesis of thyroid hormone-an essential metabolic hormone. Aberrant ...Thyroid-stimulating hormone (TSH), through activation of its G-protein-coupled thyrotropin receptor (TSHR), controls the synthesis of thyroid hormone-an essential metabolic hormone. Aberrant signalling of TSHR by autoantibodies causes Graves' disease (hyperthyroidism) and hypothyroidism, both of which affect millions of patients worldwide. Here we report the active structures of TSHR with TSH and the activating autoantibody M22, both bound to the allosteric agonist ML-109, as well as an inactivated TSHR structure with the inhibitory antibody K1-70. Both TSH and M22 push the extracellular domain (ECD) of TSHR into an upright active conformation. By contrast, K1-70 blocks TSH binding and cannot push the ECD into the upright conformation. Comparisons of the active and inactivated structures of TSHR with those of the luteinizing hormone/choriogonadotropin receptor (LHCGR) reveal a universal activation mechanism of glycoprotein hormone receptors, in which a conserved ten-residue fragment (P10) from the hinge C-terminal loop mediates ECD interactions with the TSHR transmembrane domain. One notable feature is that there are more than 15 cholesterols surrounding TSHR, supporting its preferential location in lipid rafts. These structures also highlight a similar ECD-push mechanism for TSH and autoantibody M22 to activate TSHR, therefore providing the molecular basis for Graves' disease. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_33492.map.gz | 90.1 MB | EMDB map data format | |
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Header (meta data) | emd-33492-v30.xml emd-33492.xml | 26.7 KB 26.7 KB | Display Display | EMDB header |
Images | emd_33492.png | 55 KB | ||
Others | emd_33492_additional_1.map.gz emd_33492_additional_2.map.gz emd_33492_half_map_1.map.gz emd_33492_half_map_2.map.gz | 97 MB 95.7 MB 95.5 MB 95.5 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-33492 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-33492 | HTTPS FTP |
-Related structure data
Related structure data | 7xw6MC 7xw5C 7xw7C 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_33492.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 0.824 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Additional map: #2
File | emd_33492_additional_1.map | ||||||||||||
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Density Histograms |
-Additional map: #1
File | emd_33492_additional_2.map | ||||||||||||
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Density Histograms |
-Half map: #2
File | emd_33492_half_map_1.map | ||||||||||||
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Density Histograms |
-Half map: #1
File | emd_33492_half_map_2.map | ||||||||||||
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Density Histograms |
-Sample components
+Entire : The complex was assembled by co-expression.
+Supramolecule #1: The complex was assembled by co-expression.
+Macromolecule #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
+Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Macromolecule #4: M22 antibody light chain
+Macromolecule #5: Nanobody35
+Macromolecule #6: Thyrotropin receptor
+Macromolecule #7: M22 antibody heavy chain
+Macromolecule #8: 2-acetamido-2-deoxy-beta-D-glucopyranose
+Macromolecule #9: CHOLESTEROL
+Macromolecule #10: PALMITIC ACID
+Macromolecule #11: ~{N}-[4-[[2-methoxy-5-[(2~{S})-5-oxidanyl-4-oxidanylidene-3-(phen...
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE-PROPANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Initial angle assignment | Type: RANDOM ASSIGNMENT |
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Final angle assignment | Type: MAXIMUM LIKELIHOOD |
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.78 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 455661 |