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- EMDB-25762: Human Thyrotropin receptor bound by CS-17 Inverse Agonist Fab/Org... -

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Basic information

Entry
Database: EMDB / ID: EMD-25762
TitleHuman Thyrotropin receptor bound by CS-17 Inverse Agonist Fab/Org 274179-0 Antagonist
Map dataUnsharpened map
Sample
  • Complex: Human Thyrotropin receptor in complex with the murine inverse agonist Fab fragment CS-17
    • Protein or peptide: CS-17 Heavy Chain
    • Protein or peptide: CS-17 Light Chain
    • Protein or peptide: Thyrotropin receptor
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsG protein-coupled receptor / Thyroid-stimulating hormone receptor / Thyrotropin receptor / CS-17 Fab / Thyroid / MEMBRANE PROTEIN
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 / Hormone ligand-binding receptors / G protein-coupled peptide receptor activity / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / hormone-mediated signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / cell-cell signaling ...thyroid-stimulating hormone signaling pathway / cellular response to thyrotropin-releasing hormone / thyroid-stimulating hormone receptor activity / cellular response to glycoprotein / Hormone ligand-binding receptors / G protein-coupled peptide receptor activity / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / hormone-mediated signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / cell-cell signaling / signaling receptor activity / positive regulation of cold-induced thermogenesis / G alpha (s) signalling events / basolateral plasma membrane / receptor complex / cell surface receptor signaling pathway / G protein-coupled receptor signaling pathway / positive regulation of cell population proliferation / protein-containing complex binding / cell surface / plasma membrane
Similarity search - Function
Thyrotropin receptor / BspA type Leucine rich repeat region / Glycoprotein hormone receptor family / BspA type Leucine rich repeat region (6 copies) / Leucine-rich repeat domain superfamily / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family)
Similarity search - Domain/homology
Thyrotropin receptor
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsFaust B / Cheng Y / Manglik A
Funding support United States, 2 items
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
DepositionDec 19, 2021-
Header (metadata) releaseAug 10, 2022-
Map releaseAug 10, 2022-
UpdateOct 9, 2024-
Current statusOct 9, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_25762.png

Downloads & links

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Map

FileDownload / File: emd_25762.map.gz / Format: CCP4 / Size: 343 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationUnsharpened map
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.64 Å/pix.
x 448 pix.
= 288.512 Å		0.64 Å/pix.
x 448 pix.
= 288.512 Å		0.64 Å/pix.
x 448 pix.
= 288.512 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.644 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-0.3333649 - 0.9343847
Average (Standard dev.)-0.0005714969 (±0.02339388)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions448448448
Spacing448448448
CellA=B=C: 288.512 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_25762_msk_1.map
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Additional map: Sharpened map

Fileemd_25762_additional_1.map
AnnotationSharpened map
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Half map: #1

Fileemd_25762_half_map_1.map
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Half map: #2

Fileemd_25762_half_map_2.map
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Sample components

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Entire : Human Thyrotropin receptor in complex with the murine inverse ago...

EntireName: Human Thyrotropin receptor in complex with the murine inverse agonist Fab fragment CS-17
Components
  • Complex: Human Thyrotropin receptor in complex with the murine inverse agonist Fab fragment CS-17
    • Protein or peptide: CS-17 Heavy Chain
    • Protein or peptide: CS-17 Light Chain
    • Protein or peptide: Thyrotropin receptor
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Human Thyrotropin receptor in complex with the murine inverse ago...

SupramoleculeName: Human Thyrotropin receptor in complex with the murine inverse agonist Fab fragment CS-17
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: CS-17 Heavy Chain

MacromoleculeName: CS-17 Heavy Chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.277889 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: 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

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Macromolecule #2: CS-17 Light Chain

MacromoleculeName: CS-17 Light Chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.283746 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: 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

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Macromolecule #3: Thyrotropin receptor

MacromoleculeName: Thyrotropin receptor / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 79.742375 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: 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

UniProtKB: Thyrotropin receptor

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 3 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec.
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: 2742080
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 41054
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC

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