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- EMDB-25758: Native human TSH bound to human Thyrotropin receptor in complex w... -
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Basic information
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Title | Native human TSH bound to human Thyrotropin receptor in complex with miniGs399 (composite structure) | |||||||||
![]() | Sharpened composite map | |||||||||
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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 / positive regulation of multicellular organism growth / dopaminergic neuron differentiation / G protein-coupled peptide receptor activity / response to vitamin A / regulation of signaling receptor activity / regulation of locomotion / organ growth / PKA activation in glucagon signalling / thyroid gland development / hair follicle placode formation / lateral plasma membrane / mu-type opioid receptor binding / developmental growth / corticotropin-releasing hormone receptor 1 binding / intracellular transport / D1 dopamine receptor binding / anatomical structure morphogenesis / Hedgehog 'off' state / beta-2 adrenergic receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / adenylate cyclase activator activity / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / hormone-mediated signaling pathway / adult locomotory behavior / B cell differentiation / trans-Golgi network membrane / insulin-like growth factor receptor binding / ionotropic glutamate receptor binding / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / bone development / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / hormone activity / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / cognition / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / platelet aggregation / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / response to calcium ion / cellular response to catecholamine stimulus / Golgi lumen / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / response to estrogen / 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 / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway Similarity search - Function | |||||||||
Biological species | ![]() ![]() ![]() ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.9 Å | |||||||||
![]() | Faust B / Cheng Y / Manglik A | |||||||||
Funding support | 2 items
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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. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 464.6 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 21.3 KB 21.3 KB | Display Display | ![]() |
Images | ![]() | 91.5 KB | ||
Others | ![]() | 245.9 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 441.7 KB | Display | ![]() |
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Full document | ![]() | 441.2 KB | Display | |
Data in XML | ![]() | 8 KB | Display | |
Data in CIF | ![]() | 9.2 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7t9iMC ![]() 7t9mC ![]() 7t9nC ![]() 7utzC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
EM raw data | ![]() Data size: 828.7 Data #1: Final particle stack for CS-17 Fab-bound TSHR Gs reconstruction [picked particles - single frame - processed] Data #2: Final particle stack for M22 Fab-bound TSHR-Gs reconstruction [picked particles - single frame - processed] Data #3: Final particle stack for TR1402-bound TSHR-Gs reconstruction [picked particles - single frame - processed] Data #4: Final particle stack for native human TSH-bound TSHR-Gs reconstruction [picked particles - single frame - processed]) |
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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: 0.662 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_25758_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 : Native human TSH bound to human Thyrotropin receptor in complex w...
Entire | Name: Native human TSH bound to human Thyrotropin receptor in complex with miniGs399 (composite structure) |
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Components |
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-Supramolecule #1: Native human TSH bound to human Thyrotropin receptor in complex w...
Supramolecule | Name: Native human TSH bound to human Thyrotropin receptor in complex with miniGs399 (composite structure) type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#7 |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Glycoprotein hormones alpha chain
Macromolecule | Name: Glycoprotein hormones alpha chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 10.217769 KDa |
Sequence | String: APDVQDCPEC TLQENPFFSQ PGAPILQCMG CCFSRAYPTP LRSKKTMLVQ KNVTSESTCC VAKSYNRVTV MGGFKVENHT ACHCSTCYY HKS |
-Macromolecule #2: Thyrotropin subunit beta
Macromolecule | Name: Thyrotropin subunit beta / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 12.915974 KDa |
Sequence | String: FCIPTEYTMH IERRECAYCL TINTTICAGY CMTRDINGKL FLPKYALSQD VCTYRDFIYR TVEIPGCPLH VAPYFSYPVA LSCKCGKCN TDYSDCIHEA IKTNYCTKPQ KSY |
-Macromolecule #3: Nanobody 35
Macromolecule | Name: Nanobody 35 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 15.398067 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: QVQLQESGGG LVQPGGSLRL SCAASGFTFS NYKMNWVRQA PGKGLEWVSD ISQSGASISY TGSVKGRFTI SRDNAKNTLY LQMNSLKPE DTAVYYCARC PAPFTRDCFD VTSTTYAYRG QGTQVTVSSG SEDQVDPRLI DGK |
-Macromolecule #4: Thyrotropin receptor
Macromolecule | Name: Thyrotropin receptor / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 79.742375 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: DYKDDDDGTM GCSSPPCECH QEEDFRVTCK DIQRIPSLPP STQTLKLIET HLRTIPSHAF SNLPNISRIY VSIDVTLQQL ESHSFYNLS KVTHIEIRNT RNLTYIDPDA LKELPLLKFL GIFNTGLKMF PDLTKVYSTD IFFILEITDN PYMTSIPVNA F QGLCNETL ...String: DYKDDDDGTM GCSSPPCECH QEEDFRVTCK DIQRIPSLPP STQTLKLIET HLRTIPSHAF SNLPNISRIY VSIDVTLQQL ESHSFYNLS KVTHIEIRNT RNLTYIDPDA LKELPLLKFL GIFNTGLKMF PDLTKVYSTD IFFILEITDN PYMTSIPVNA F QGLCNETL TLKLYNNGFT SVQGYAFNGT KLDAVYLNKN KYLTVIDKDA FGGVYSGPSL LDVSQTSVTA LPSKGLEHLK EL IARNTWT LKKLPLSLSF LHLTRADLSY PSHCCAFKNQ KKIRGILESL MCNESSMQSL RQRKSVNGQE LKNPQEETLQ AFD SHYDYT ICGDSEDMVC TPKSDEFNPC EDIMGYKFLR IVVWFVSLLA LLGNVFVLLI LLTSHYKLNV PRFLMCNLAF ADFC MGMYL LLIASVDLYT HSEYYNHAID WQTGPGCNTA GFFTVFASEL SVYTLTVITL ERWYAITFAM RLDRKIRLRH ACAIM VGGW VCCFLLALLP LVGISSYAKV SICLPMDTET PLALAYIVFV LTLNIVAFVI VCCCYVKIYI TVRNPQYNPG DKDTKI AKR MAVLIFTDFI CMAPISFYAL SAILNKPLIT VSNSKILLVL FYPLNSCANP FLYAIFTKAF QRDVFILLSK FGICKRQ AQ AYRGQRVPPK NSTDIQVQKV THEMRQGLHN MEDVYELIEN SHLTPKKQGQ ISEEYMQTVL |
-Macromolecule #5: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Macromolecule | Name: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 30.137025 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: GGSLEVLFQG PSGNSKTEDQ RNEEKAQREA NKKIEKQLQK DKQVYRATHR LLLLGADNSG KSTIVKQMRI LHGGSGGSGG TSGIFETKF QVDKVNFHMF DVGGQRDERR KWIQCFNDVT AIIFVVDSSD YNRLQEALNL FKSIWNNRWL RTISVILFLN K QDLLAEKV ...String: GGSLEVLFQG PSGNSKTEDQ RNEEKAQREA NKKIEKQLQK DKQVYRATHR LLLLGADNSG KSTIVKQMRI LHGGSGGSGG TSGIFETKF QVDKVNFHMF DVGGQRDERR KWIQCFNDVT AIIFVVDSSD YNRLQEALNL FKSIWNNRWL RTISVILFLN K QDLLAEKV LAGKSKLEDY FPEFARYTTP EDATPEPGED PRVTRAKYFI RDEFLRISTA SGDGRHYCYP HFTCAVDTEN AR RIFNDCR DIIQRMHLRQ YELL |
-Macromolecule #6: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 40.786566 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MHHHHHHLEV LFQGPEDQVD PRLIDGKGSS GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIY AMHWGTDSRL LVSASQDGKL IIWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR E GNVRVSRE ...String: MHHHHHHLEV LFQGPEDQVD PRLIDGKGSS GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIY AMHWGTDSRL LVSASQDGKL IIWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR E GNVRVSRE LAGHTGYLSC CRFLDDNQIV TSSGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KL WDVREGM CRQTFTGHES DINAICFFPN GNAFATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYD DFNCNV WDALKADRAG VLAGHDNRVS CLGVTDDGMA VATGSWDSFL KIWN |
-Macromolecule #7: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 type: protein_or_peptide / ID: 7 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 7.861143 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L |
-Macromolecule #9: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 9 / Number of copies: 6 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-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: 77.0 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: 130000 |
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-7t9i: |