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Yorodumi- EMDB-25762: Human Thyrotropin receptor bound by CS-17 Inverse Agonist Fab/Org... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-25762 | |||||||||
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Title | Human Thyrotropin receptor bound by CS-17 Inverse Agonist Fab/Org 274179-0 Antagonist | |||||||||
Map data | Unsharpened map | |||||||||
Sample |
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Function / homology | Function and homology information thyroid-stimulating hormone receptor activity / cochlea morphogenesis / inner ear receptor cell stereocilium organization / positive regulation of multicellular organism growth / dopaminergic neuron differentiation / G protein-coupled peptide receptor activity / regulation of locomotion / lateral plasma membrane / hormone-mediated signaling pathway / adult locomotory behavior ...thyroid-stimulating hormone receptor activity / cochlea morphogenesis / inner ear receptor cell stereocilium organization / positive regulation of multicellular organism growth / dopaminergic neuron differentiation / G protein-coupled peptide receptor activity / regulation of locomotion / lateral plasma membrane / hormone-mediated signaling pathway / adult locomotory behavior / B cell differentiation / adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of cold-induced thermogenesis / basolateral plasma membrane Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Mus musculus (house mouse) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.1 Å | |||||||||
Authors | Faust B / Cheng Y / Manglik A | |||||||||
Funding support | United States, 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_25762.map.gz | 168.8 MB | EMDB map data format | |
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Header (meta data) | emd-25762-v30.xml emd-25762.xml | 21.4 KB 21.4 KB | Display Display | EMDB header |
Images | emd_25762.png | 118.3 KB | ||
Masks | emd_25762_msk_1.map | 343 MB | Mask map | |
Others | emd_25762_additional_1.map.gz emd_25762_half_map_1.map.gz emd_25762_half_map_2.map.gz | 323.5 MB 318.2 MB 318.2 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-25762 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-25762 | HTTPS FTP |
-Validation report
Summary document | emd_25762_validation.pdf.gz | 788.2 KB | Display | EMDB validaton report |
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Full document | emd_25762_full_validation.pdf.gz | 787.8 KB | Display | |
Data in XML | emd_25762_validation.xml.gz | 17.3 KB | Display | |
Data in CIF | emd_25762_validation.cif.gz | 20.6 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-25762 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-25762 | HTTPS FTP |
-Related structure data
Related structure data | 7t9mMC 7t9iC 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 |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_25762.map.gz / Format: CCP4 / Size: 343 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Annotation | Unsharpened map | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.644 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
File | emd_25762_msk_1.map | ||||||||||||
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Density Histograms |
-Additional map: Sharpened map
File | emd_25762_additional_1.map | ||||||||||||
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Annotation | Sharpened map | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_25762_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_25762_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Human Thyrotropin receptor in complex with the murine inverse ago...
Entire | Name: Human Thyrotropin receptor in complex with the murine inverse agonist Fab fragment CS-17 |
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Components |
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-Supramolecule #1: Human Thyrotropin receptor in complex with the murine inverse ago...
Supramolecule | Name: Human Thyrotropin receptor in complex with the murine inverse agonist Fab fragment CS-17 type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: CS-17 Heavy Chain
Macromolecule | Name: CS-17 Heavy Chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 23.277889 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: EVQLQQSGPE LVKPGASVKM SCKASGYTFT SYIIHWVKQK PGQGLEWIGY INLYNDGTNY NEKFTGKATL TSDKSSSTAY MELSSLTSE DSAVYYCARE DYYGRVADFD VWGAGTTVTV SSKTTAPSVY PLAPVCGDTT GSSVTLGCLV KGYFPEPVTL T WNSGSLSS ...String: EVQLQQSGPE LVKPGASVKM SCKASGYTFT SYIIHWVKQK PGQGLEWIGY INLYNDGTNY NEKFTGKATL TSDKSSSTAY MELSSLTSE DSAVYYCARE DYYGRVADFD VWGAGTTVTV SSKTTAPSVY PLAPVCGDTT GSSVTLGCLV KGYFPEPVTL T WNSGSLSS GVHTFPAVLQ SDLYTLSSSV TVTSSTWPSQ SITCNVAHPA SSTKVDKKI |
-Macromolecule #2: CS-17 Light Chain
Macromolecule | Name: CS-17 Light Chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 23.283746 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: HLVLTQSPAI MSASPGEKVT ISCSASSSVS YMCWFQQKPG SSPKPWIYRT SNLASGVPAR FSGSGSGTSY SLTISSMEAE DAATYYCQQ YHSYPLTFGA GTKLELKRAD AAPTVSIFPP SSEQLTSGGA SVVCFLNNFY PKDINVKWKI DGSERQNGVL N SWTDQDSK ...String: HLVLTQSPAI MSASPGEKVT ISCSASSSVS YMCWFQQKPG SSPKPWIYRT SNLASGVPAR FSGSGSGTSY SLTISSMEAE DAATYYCQQ YHSYPLTFGA GTKLELKRAD AAPTVSIFPP SSEQLTSGGA SVVCFLNNFY PKDINVKWKI DGSERQNGVL N SWTDQDSK DSTYSMSSTL TLTKDEYERH NSYTCEATHK TSTSPIVKSF NRNEC |
-Macromolecule #3: Thyrotropin receptor
Macromolecule | Name: Thyrotropin receptor / type: protein_or_peptide / ID: 3 / 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: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 3 / 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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Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE |
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 |