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Yorodumi- EMDB-25758: Native human TSH bound to human Thyrotropin receptor in complex w... -
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-Basic information
Entry | Database: EMDB / ID: EMD-25758 | |||||||||
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Title | Native human TSH bound to human Thyrotropin receptor in complex with miniGs399 (composite structure) | |||||||||
Map data | Sharpened composite map | |||||||||
Sample |
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Function / homology | Function and homology information 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 / dopaminergic neuron differentiation / positive regulation of multicellular organism growth / regulation of signaling receptor activity / response to vitamin A / regulation of locomotion / organ growth / PKA activation in glucagon signalling / thyroid gland development / hair follicle placode formation / lateral plasma membrane / developmental growth / D1 dopamine receptor binding / intracellular transport / anatomical structure morphogenesis / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / hormone-mediated signaling pathway / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / adenylate cyclase activator activity / B cell differentiation / adult locomotory behavior / trans-Golgi network membrane / response to calcium ion / G-protein beta/gamma-subunit complex binding / bone development / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / hormone activity / 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 / cognition / platelet aggregation / 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 / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Golgi lumen / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / response to estrogen / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / 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 / Ca2+ pathway / positive regulation of cold-induced thermogenesis / phospholipase C-activating G protein-coupled receptor signaling pathway / basolateral plasma membrane / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / human (human) / Lama glama (llama) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.9 Å | |||||||||
Authors | Faust B / Cheng Y / Manglik A | |||||||||
Funding support | 2 items
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Citation | Journal: 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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_25758.map.gz | 464.6 MB | EMDB map data format | |
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Header (meta data) | emd-25758-v30.xml emd-25758.xml | 21.3 KB 21.3 KB | Display Display | EMDB header |
Images | emd_25758.png | 91.5 KB | ||
Others | emd_25758_additional_1.map.gz | 245.9 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-25758 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-25758 | HTTPS FTP |
-Validation report
Summary document | emd_25758_validation.pdf.gz | 441.7 KB | Display | EMDB validaton report |
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Full document | emd_25758_full_validation.pdf.gz | 441.2 KB | Display | |
Data in XML | emd_25758_validation.xml.gz | 8 KB | Display | |
Data in CIF | emd_25758_validation.cif.gz | 9.2 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-25758 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-25758 | HTTPS FTP |
-Related structure data
Related structure data | 7t9iMC 7t9mC 7t9nC 7utzC 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 |
EM raw data | EMPIAR-11120 (Title: Single-particle cryo-electron microscopy final particle stacks and .star files from TSHR complexes 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]) |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_25758.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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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 |
-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: Homo sapiens (human) |
-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: human (human) |
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: human (human) |
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: Lama glama (llama) |
Molecular weight | Theoretical: 15.398067 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
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: Homo sapiens (human) |
Molecular weight | Theoretical: 79.742375 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
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: Homo sapiens (human) |
Molecular weight | Theoretical: 30.137025 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
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: Homo sapiens (human) |
Molecular weight | Theoretical: 40.786566 KDa |
Recombinant expression | Organism: Trichoplusia ni (cabbage looper) |
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: Homo sapiens (human) |
Molecular weight | Theoretical: 7.861143 KDa |
Recombinant expression | Organism: Trichoplusia ni (cabbage looper) |
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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Processing | single particle reconstruction |
Aggregation state | particle |
-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 |
-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: FIELD EMISSION GUN |
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 |
+Image processing
-Atomic model buiding 1
Refinement | Protocol: FLEXIBLE FIT |
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Output model | PDB-7t9i: |