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- EMDB-27650: Native human TSH bound to human Thyrotropin receptor (transmembra... -

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Basic information

Entry
Database: EMDB / ID: EMD-27650
TitleNative human TSH bound to human Thyrotropin receptor (transmembrane domain and G protein map only)
Map data
Sample
  • Complex: Native human TSH bound to human Thyrotropin receptor in complex with miniGs399 (composite structure)
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsFaust B / Cheng Y / Manglik A
Funding support2 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI)
National Institutes of Health/National Cancer Institute (NIH/NCI)
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
DepositionJul 18, 2022-
Header (metadata) releaseAug 24, 2022-
Map releaseAug 24, 2022-
UpdateOct 5, 2022-
Current statusOct 5, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27650.png

Downloads & links

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Map

FileDownload / File: emd_27650.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.66 Å/pix.
x 512 pix.
= 338.944 Å		0.66 Å/pix.
x 512 pix.
= 338.944 Å		0.66 Å/pix.
x 512 pix.
= 338.944 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.662 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.41
Minimum - Maximum-2.0270045 - 3.1070826
Average (Standard dev.)-0.00073961593 (±0.04295133)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 338.944 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_27650_msk_1.map
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AxesZYX

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Half map: #1

Fileemd_27650_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #2

Fileemd_27650_half_map_2.map
Projections & Slices
AxesZYX

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Sample components

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Entire : Native human TSH bound to human Thyrotropin receptor in complex w...

EntireName: Native human TSH bound to human Thyrotropin receptor in complex with miniGs399 (composite structure)
Components
  • Complex: Native human TSH bound to human Thyrotropin receptor in complex with miniGs399 (composite structure)

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Supramolecule #1: Native human TSH bound to human Thyrotropin receptor in complex w...

SupramoleculeName: 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
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant strain: expi293

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 77.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 130000
Sample stageSpecimen 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

Particle selectionNumber selected: 6185950
CTF correctionSoftware - Name: cryoSPARC
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 80483
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC

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