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- EMDB-33493: TSHR-K1-70 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-33493
TitleTSHR-K1-70 complex
Map data
Sample
  • Complex: TSHR-thyroid stimulating hormone-Gs-ML109 complex
    • Protein or peptide: Thyrotropin receptor
  • Protein or peptide: K1-70 scFv
Keywordsthyroid-stimulating hormone / thyroid-stimulating hormone receptor / THS / THSR / GPCR / Gs / k1-70 / MEMBRANE PROTEIN
Function / homology
Function and homology information


thyroid-stimulating hormone signaling pathway / cellular response to glycoprotein / cellular response to thyrotropin-releasing hormone / thyroid-stimulating hormone receptor activity / 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 glycoprotein / cellular response to thyrotropin-releasing hormone / thyroid-stimulating hormone receptor activity / 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 / cell surface receptor signaling pathway / receptor complex / 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 / Glycoprotein hormone receptor family / BspA type Leucine rich repeat region / 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 (humans) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.5 Å
AuthorsDuan J / Xu P / Luan X / Ji Y / Yuan Q / He X / Ye J / Cheng X / Jiang H / Zhang S ...Duan J / Xu P / Luan X / Ji Y / Yuan Q / He X / Ye J / Cheng X / Jiang H / Zhang S / Jiang Y / Xu HE
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32130022 China
CitationJournal: Nature / Year: 2022
Title: Hormone- and antibody-mediated activation of the thyrotropin receptor.
Authors: Jia Duan / Peiyu Xu / Xiaodong Luan / Yujie Ji / Xinheng He / Ning Song / Qingning Yuan / Ye Jin / Xi Cheng / Hualiang Jiang / Jie Zheng / Shuyang Zhang / Yi Jiang / H Eric Xu /
Abstract: Thyroid-stimulating hormone (TSH), through activation of its G-protein-coupled thyrotropin receptor (TSHR), controls the synthesis of thyroid hormone-an essential metabolic hormone. Aberrant ...Thyroid-stimulating hormone (TSH), through activation of its G-protein-coupled thyrotropin receptor (TSHR), controls the synthesis of thyroid hormone-an essential metabolic hormone. Aberrant signalling of TSHR by autoantibodies causes Graves' disease (hyperthyroidism) and hypothyroidism, both of which affect millions of patients worldwide. Here we report the active structures of TSHR with TSH and the activating autoantibody M22, both bound to the allosteric agonist ML-109, as well as an inactivated TSHR structure with the inhibitory antibody K1-70. Both TSH and M22 push the extracellular domain (ECD) of TSHR into an upright active conformation. By contrast, K1-70 blocks TSH binding and cannot push the ECD into the upright conformation. Comparisons of the active and inactivated structures of TSHR with those of the luteinizing hormone/choriogonadotropin receptor (LHCGR) reveal a universal activation mechanism of glycoprotein hormone receptors, in which a conserved ten-residue fragment (P10) from the hinge C-terminal loop mediates ECD interactions with the TSHR transmembrane domain. One notable feature is that there are more than 15 cholesterols surrounding TSHR, supporting its preferential location in lipid rafts. These structures also highlight a similar ECD-push mechanism for TSH and autoantibody M22 to activate TSHR, therefore providing the molecular basis for Graves' disease.
History
DepositionMay 26, 2022-
Header (metadata) releaseAug 17, 2022-
Map releaseAug 17, 2022-
UpdateMar 13, 2024-
Current statusMar 13, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33493.png

Downloads & links

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Map

FileDownload / File: emd_33493.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.04 Å
Density
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.0020833781 - 1.4259893
Average (Standard dev.)0.0060049323 (±0.043728396)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 208.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_33493_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_33493_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : TSHR-thyroid stimulating hormone-Gs-ML109 complex

EntireName: TSHR-thyroid stimulating hormone-Gs-ML109 complex
Components
  • Complex: TSHR-thyroid stimulating hormone-Gs-ML109 complex
    • Protein or peptide: Thyrotropin receptor
  • Protein or peptide: K1-70 scFv

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Supramolecule #1: TSHR-thyroid stimulating hormone-Gs-ML109 complex

SupramoleculeName: TSHR-thyroid stimulating hormone-Gs-ML109 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #2
Source (natural)Organism: Homo (humans)

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Macromolecule #1: K1-70 scFv

MacromoleculeName: K1-70 scFv / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.400182 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: EVQLVQSGAE VKKPGQSLKI SCKASGYSLT DNWIGWVRQK PGKGLEWMGI IYPGDSDTRY SPSFQGQVTI SADKSINTAY LQWSSLKAS DTAIYYCVGL DWNYNPLRYW GPGTLVTVSS VLTQPPSVSA APGQKVTISC SGSSSDIGSN YVSWYQQFPG T APKLLIYD ...String:
EVQLVQSGAE VKKPGQSLKI SCKASGYSLT DNWIGWVRQK PGKGLEWMGI IYPGDSDTRY SPSFQGQVTI SADKSINTAY LQWSSLKAS DTAIYYCVGL DWNYNPLRYW GPGTLVTVSS VLTQPPSVSA APGQKVTISC SGSSSDIGSN YVSWYQQFPG T APKLLIYD NNKRPSAIPD RFSGSKSGTS ATLGITGLQT GDEADYYCGT WDSRLGIAVF GGGTQLTVL

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Macromolecule #2: Thyrotropin receptor

MacromoleculeName: Thyrotropin receptor / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 79.894734 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GMGCSSPPCE CHQEEDFRVT CKDIQRIPSL PPSTQTLKLI ETHLRTIPSH AFSNLPNISR IYVSIDVTLQ QLESHSFYNL SKVTHIEIR NTRNLTYIDP DALKELPLLK FLGIFNTGLK MFPDLTKVYS TDIFFILEIT DNPYMTSIPV NAFQGLCNET L TLKLYNNG ...String:
GMGCSSPPCE CHQEEDFRVT CKDIQRIPSL PPSTQTLKLI ETHLRTIPSH AFSNLPNISR IYVSIDVTLQ QLESHSFYNL SKVTHIEIR NTRNLTYIDP DALKELPLLK FLGIFNTGLK MFPDLTKVYS TDIFFILEIT DNPYMTSIPV NAFQGLCNET L TLKLYNNG FTSVQGYAFN GTKLDAVYLN KNKYLTVIDK DAFGGVYSGP SLLDVSQTSV TALPSKGLEH LKELIARNTW TL KKLPLSL SFLHLTRADL SYPSHCCAFK NQKKIRGILE SLMCNESSMQ SLRQRKSVNN KTLKNPQEET LQAFDSHYDY TIC GDSEDM VCTPKSDEFN PCEDIMGYKF LRIVVWFVSL LALLGNVFVL LILLTSHYKL NVPRFLMCNL AFADFCMGMY LLLI ASVDL YTHSEYYNHA IDWQTGPGCN TAGFFTVFAS ELSVYTLTVI TLERWYAITF AMRLDRKIRL RHACAIMVGG WVCCF LLAL LPLVGISSYA KVSICLPMDT ETPLALAYIV FVLTLNIVAF VIVCCCYVKI YITVRNPQYN PGDKDTKIAK RMAVLI FTD FICMAPISFY ALSAILNKPL ITVSNSKILL VLFYPLNSCA NPFLYAIFTK AFQRDVFILL SKFGICKRQA QAYRGQR VP PKNSTDIQVQ KVTHDMRQGL HNMEDVYELI ENSHLTPKKQ GQISEEYMQT VLHHHHHHHH

UniProtKB: Thyrotropin receptor

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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: 7.4
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

31598

Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 5.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 52479

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