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- PDB-7utz: Human thyrotropin analog TR1402 bound to human Thyrotropin recept... -

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Basic information

Entry
Database: PDB / ID: 7utz
TitleHuman thyrotropin analog TR1402 bound to human Thyrotropin receptor in complex with miniGs399 (composite structure)
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Glycoprotein hormones alpha chain analog TR1402
  • Nanobody 35
  • Thyrotropin receptor
  • Thyrotropin subunit beta
KeywordsMEMBRANE PROTEIN / G protein-coupled receptor / Thyroid-stimulating hormone receptor / Thyrotropin receptor / TSH / Thyroid
Function / homology
Function and homology information


thyroid-stimulating hormone signaling pathway / cellular response to thyrotropin-releasing hormone / thyroid-stimulating hormone receptor activity / cellular response to glycoprotein / positive regulation of steroid biosynthetic process / follicle-stimulating hormone activity / follicle-stimulating hormone complex / pituitary gonadotropin complex / Mineralocorticoid biosynthesis / Thyroxine biosynthesis ...thyroid-stimulating hormone signaling pathway / cellular response to thyrotropin-releasing hormone / thyroid-stimulating hormone receptor activity / cellular response to glycoprotein / positive regulation of steroid biosynthetic process / follicle-stimulating hormone activity / follicle-stimulating hormone complex / pituitary gonadotropin complex / Mineralocorticoid biosynthesis / Thyroxine biosynthesis / regulation of signaling receptor activity / Glycoprotein hormones / Hormone ligand-binding receptors / Reactions specific to the complex N-glycan synthesis pathway / Androgen biosynthesis / follicle-stimulating hormone signaling pathway / insulin secretion involved in cellular response to glucose stimulus / G protein-coupled peptide receptor activity / adenylate cyclase-activating G protein-coupled bile acid receptor signaling pathway / adenylate cyclase-activating serotonin receptor signaling pathway / intracellular transport / regulation of skeletal muscle contraction / hair follicle placode formation / developmental growth / PKA activation in glucagon signalling / renal water homeostasis / anatomical structure morphogenesis / D1 dopamine receptor binding / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / vascular endothelial cell response to laminar fluid shear stress / hormone-mediated signaling pathway / Hedgehog 'off' state / activation of adenylate cyclase activity / adenylate cyclase-activating adrenergic receptor signaling pathway / cellular response to acidic pH / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / ovarian follicle development / cellular response to glucagon stimulus / intracellular glucose homeostasis / adenylate cyclase activator activity / positive regulation of insulin secretion involved in cellular response to glucose stimulus / trans-Golgi network membrane / positive regulation of insulin secretion / negative regulation of inflammatory response to antigenic stimulus / response to prostaglandin E / hormone activity / bone development / platelet aggregation / Golgi lumen / cognition / G protein-coupled receptor activity / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / sensory perception of smell / G protein-coupled acetylcholine receptor signaling pathway / MAPK cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / cell-cell signaling / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / positive regulation of cold-induced thermogenesis / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / heterotrimeric G-protein complex / G alpha (12/13) signalling events / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / signaling receptor activity / extracellular vesicle / Thrombin signalling through proteinase activated receptors (PARs) / adenylate cyclase-activating G protein-coupled receptor signaling pathway / signaling receptor complex adaptor activity / GTPase binding / G protein activity / spermatogenesis / Ca2+ pathway / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells
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 / BspA type Leucine rich repeat region / Cystine-knot domain / BspA type Leucine rich repeat region (6 copies) / Glycoprotein hormone receptor family / Leucine-rich repeat, LRR (right-handed beta-alpha superhelix) / Ribonuclease Inhibitor / Cystine-knot cytokine / Alpha-Beta Horseshoe / Rhopdopsin 7-helix transmembrane proteins / Rhodopsin 7-helix transmembrane proteins / G-protein alpha subunit, group S / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / Leucine-rich repeat domain superfamily / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit / G protein beta WD-40 repeat protein / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / P-loop containing nucleotide triphosphate hydrolases / 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. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Immunoglobulins / Up-down Bundle / Immunoglobulin-like / Sandwich / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
(2S)-3-hydroxypropane-1,2-diyl dihexadecanoate / Thyrotropin receptor / Glycoprotein hormones alpha chain / Thyrotropin subunit beta / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.4 Å
AuthorsFaust, B. / Cheng, Y. / Manglik, A.
Funding support United States, 2items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: 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
DepositionApr 28, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 3, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 24, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 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
Revision 1.3Oct 23, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Glycoprotein hormones alpha chain analog TR1402
B: Thyrotropin subunit beta
N: Nanobody 35
R: Thyrotropin receptor
X: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Y: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Z: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)199,22115
Polymers197,1047
Non-polymers2,1178
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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Protein , 3 types, 3 molecules ABR

#1: Protein Glycoprotein hormones alpha chain analog TR1402 / 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: 10364.058 Da / Num. of mol.: 1 / Mutation: Q13R, E14R, P16R, Q20R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CGA / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P01215
#2: Protein Thyrotropin subunit beta / Thyroid-stimulating hormone subunit beta / TSH-B / TSH-beta / Thyrotropin beta chain


Mass: 12915.974 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TSHB / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P01222
#4: Protein Thyrotropin receptor


Mass: 79641.273 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TSHR / Production host: Homo sapiens (human) / References: UniProt: A0A0A0MTJ0

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

#5: Protein Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Adenylate cyclase-stimulating G alpha protein


Mass: 30137.025 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Production host: Homo sapiens (human) / References: UniProt: P63092
#6: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 40786.566 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Homo sapiens (human) / References: UniProt: P62873
#7: 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: Homo sapiens (human) / References: UniProt: P59768

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Antibody / Sugars / Non-polymers , 3 types, 9 molecules N

#3: Antibody Nanobody 35


Mass: 15398.067 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#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
#9: Chemical ChemComp-Z41 / (2S)-3-hydroxypropane-1,2-diyl dihexadecanoate


Mass: 568.911 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H68O5

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Details

Has ligand of interestY
Has protein modificationY

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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: Human TSH analog TR1402 bound to human Thyrotropin receptor in complex with miniGs399 (composite structure)
Type: COMPLEX / Entity ID: #1-#7 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Strain: expi293
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

SoftwareName: PHENIX / Version: 1.19.1_4122: / Classification: refinement
EM software
IDNameVersionCategory
2SerialEMimage acquisition
4cryoSPARCCTF correction
9PHENIX1.19.2model refinement
10ISOLDE1.2model refinement
11cryoSPARCinitial Euler assignment
12cryoSPARCfinal Euler assignment
14cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 7940651
3D reconstructionResolution: 2.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 375930
Details: 2.4A GS-FSC refers to Thyrotropin receptor transmembrane domain in complex with heterotrimeric G proteins. Extracellular domain in complex with TR1402 TSH analog GS-FSC is 2.7A.
Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00412315
ELECTRON MICROSCOPYf_angle_d0.65516718
ELECTRON MICROSCOPYf_dihedral_angle_d6.0521760
ELECTRON MICROSCOPYf_chiral_restr0.0441939
ELECTRON MICROSCOPYf_plane_restr0.0062111

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