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- PDB-7xw5: TSHR-thyroid stimulating hormone-Gs-ML109 complex -

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Basic information

Entry
Database: PDB / ID: 7xw5
TitleTSHR-thyroid stimulating hormone-Gs-ML109 complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Glycoprotein hormones alpha chain
  • Nanobody35
  • Thyrotropin receptor
  • Thyrotropin subunit beta
KeywordsMEMBRANE PROTEIN / thyroid-stimulating hormone / thyroid-stimulating hormone receptor / THS / THSR / GPCR / Gs / ML-109
Function / homology
Function and homology information


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
Thyrotropin receptor / Gonadotropin, beta subunit, conserved site / Glycoprotein hormones beta chain signature 1. / Glycoprotein hormones beta chain signature 2. / Glycoprotein hormone beta chain homologues. / Glycoprotein hormone alpha chain / Glycoprotein hormone / Glycoprotein hormones alpha chain signature 1. / Glycoprotein hormones alpha chain signature 2. / Glycoprotein hormones alpha chain family profile. ...Thyrotropin receptor / Gonadotropin, beta subunit, conserved site / Glycoprotein hormones beta chain signature 1. / Glycoprotein hormones beta chain signature 2. / Glycoprotein hormone beta chain homologues. / Glycoprotein hormone alpha chain / Glycoprotein hormone / Glycoprotein hormones alpha chain signature 1. / Glycoprotein hormones alpha chain signature 2. / Glycoprotein hormones alpha chain family profile. / Glycoprotein hormone alpha chain homologues. / Gonadotropin, beta subunit / Glycoprotein hormone subunit beta / Cystine-knot domain / Glycoprotein hormone receptor family / BspA type Leucine rich repeat region / BspA type Leucine rich repeat region (6 copies) / Cystine-knot cytokine / G-protein alpha subunit, group S / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / Leucine-rich repeat domain superfamily / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
CHOLESTEROL / Chem-HOI / PALMITIC ACID / Glycoprotein hormones alpha chain / Thyrotropin subunit beta / Thyrotropin receptor / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.96 Å
AuthorsDuan, 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 China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32130022 China
CitationJournal: 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
DepositionMay 26, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 24, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 5, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
N: Nanobody35
R: Thyrotropin receptor
X: Glycoprotein hormones alpha chain
Y: Thyrotropin subunit beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)202,68234
Polymers193,9157
Non-polymers8,76727
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#1: Protein Guanine nucleotide-binding protein G(s) subunit alpha isoforms short


Mass: 29068.906 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63094
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 38613.176 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


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: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Protein , 3 types, 3 molecules RXY

#5: Protein Thyrotropin receptor / Thyroid-stimulating hormone receptor / TSH-R


Mass: 79920.812 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TSHR, LGR3 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P16473
#6: Protein Glycoprotein hormones alpha chain / Anterior pituitary glycoprotein hormones common subunit alpha / Choriogonadotropin alpha chain / ...Anterior pituitary glycoprotein hormones common subunit alpha / Choriogonadotropin alpha chain / Chorionic gonadotrophin subunit alpha / CG-alpha / Follicle-stimulating hormone alpha chain / FSH-alpha / Follitropin alpha chain / Luteinizing hormone alpha chain / LSH-alpha / Lutropin alpha chain / Thyroid-stimulating hormone alpha chain / TSH-alpha / Thyrotropin alpha chain


Mass: 10217.769 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CGA / Production host: Homo sapiens (human) / References: UniProt: P01215
#7: Protein Thyrotropin subunit beta / Thyroid-stimulating hormone subunit beta / TSH-B / TSH-beta / Thyrotropin beta chain


Mass: 13518.698 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TSHB / Production host: Homo sapiens (human) / References: UniProt: P01222

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Antibody / Sugars , 2 types, 8 molecules N

#4: Antibody Nanobody35


Mass: 14714.320 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
#8: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 3 types, 20 molecules

#9: Chemical ChemComp-HOI / ~{N}-[4-[[2-methoxy-5-[(2~{S})-5-oxidanyl-4-oxidanylidene-3-(phenylmethyl)-1,2-dihydroquinazolin-2-yl]phenyl]methoxy]phenyl]ethanamide


Mass: 523.579 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H29N3O5 / Feature type: SUBJECT OF INVESTIGATION
#10: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: C27H46O
#11: Chemical
ChemComp-PLM / PALMITIC ACID


Mass: 256.424 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C16H32O2

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: TSHR-thyroid stimulating hormone-Gs-ML109 complex / Type: COMPLEX / Entity ID: #1-#7 / Source: RECOMBINANT
Source (natural)Organism: Homo (humans)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.96 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 565098 / Symmetry type: POINT

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