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Open data
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Basic information
Entry | Database: PDB / ID: 7xw5 | ||||||
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Title | TSHR-thyroid stimulating hormone-Gs-ML109 complex | ||||||
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![]() | MEMBRANE PROTEIN / thyroid-stimulating hormone / thyroid-stimulating hormone receptor / THS / THSR / GPCR / Gs / ML-109 | ||||||
Function / homology | ![]() regulation of parathyroid hormone secretion / COPI-coated Golgi to ER transport vesicle / : / negative regulation of renal sodium excretion / thyroid-stimulating hormone signaling pathway / cellular response to glycoprotein / cellular response to thyrotropin-releasing hormone / post-embryonic body morphogenesis / thyroid-stimulating hormone receptor activity / follicle-stimulating hormone activity ...regulation of parathyroid hormone secretion / COPI-coated Golgi to ER transport vesicle / : / negative regulation of renal sodium excretion / thyroid-stimulating hormone signaling pathway / cellular response to glycoprotein / cellular response to thyrotropin-releasing hormone / post-embryonic body morphogenesis / 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 / response to parathyroid hormone / genomic imprinting / negative regulation of organ growth / positive regulation of cAMP-mediated signaling / sensory perception of chemical stimulus / tissue homeostasis / energy reserve metabolic process / positive regulation of sodium ion transport / endochondral ossification / thyroid hormone generation / G protein-coupled peptide receptor activity / positive regulation of osteoclast differentiation / embryonic cranial skeleton morphogenesis / response to vitamin A / regulation of signaling receptor activity / embryonic hindlimb morphogenesis / cartilage development / alkylglycerophosphoethanolamine phosphodiesterase activity / skin development / organ growth / thyroid gland development / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / hair follicle placode formation / alpha-tubulin binding / mu-type opioid receptor binding / developmental growth / corticotropin-releasing hormone receptor 1 binding / G-protein alpha-subunit binding / regulation of signal transduction / D1 dopamine receptor binding / anatomical structure morphogenesis / calcium ion homeostasis / positive regulation of osteoblast differentiation / beta-2 adrenergic receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / ruffle / adenylate cyclase activator activity / negative regulation of blood pressure / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / hormone-mediated signaling pathway / post-embryonic development / positive regulation of GTPase activity / trans-Golgi network membrane / skeletal system development / G protein-coupled receptor binding / ionotropic glutamate receptor binding / insulin-like growth factor receptor binding / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / bone development / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / multicellular organism growth / G-protein activation / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / hormone activity / recycling endosome / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / sarcolemma / 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 Similarity search - Function | ||||||
Biological species | ![]() ![]() ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.96 Å | ||||||
![]() | 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, H.E. | ||||||
Funding support | ![]()
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![]() | ![]() 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
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 324.5 KB | Display | ![]() |
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PDB format | ![]() | 263.5 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1.8 MB | Display | ![]() |
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Full document | ![]() | 1.8 MB | Display | |
Data in XML | ![]() | 54.2 KB | Display | |
Data in CIF | ![]() | 80.1 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 33491MC ![]() 7xw6C ![]() 7xw7C M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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1 |
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Components
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG
#1: Protein | Mass: 29068.906 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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#2: Protein | Mass: 38613.176 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
#3: Protein | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
-Protein , 3 types, 3 molecules RXY
#5: Protein | Mass: 79920.812 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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#6: Protein | Mass: 10217.769 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
#7: Protein | Mass: 13518.698 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
-Antibody / Sugars , 2 types, 8 molecules N![](data/chem/img/NAG.gif)
![](data/chem/img/NAG.gif)
#4: Antibody | Mass: 14714.320 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() |
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#8: Sugar | ChemComp-NAG / |
-Non-polymers , 3 types, 20 molecules ![](data/chem/img/HOI.gif)
![](data/chem/img/CLR.gif)
![](data/chem/img/PLM.gif)
![](data/chem/img/CLR.gif)
![](data/chem/img/PLM.gif)
#9: Chemical | ChemComp-HOI / ~{ | ||
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#10: Chemical | ChemComp-CLR / #11: Chemical | ChemComp-PLM / |
-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 |
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Sample preparation
Component | Name: TSHR-thyroid stimulating hormone-Gs-ML109 complex / Type: COMPLEX / Entity ID: #1-#7 / Source: RECOMBINANT |
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Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE-PROPANE |
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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: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm |
Image recording | Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
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Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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3D reconstruction | Resolution: 2.96 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 565098 / Symmetry type: POINT |