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- EMDB-37358: Cryo-EM structure of the AA14-bound GPR101 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-37358
TitleCryo-EM structure of the AA14-bound GPR101 complex
Map data
Sample
  • Complex: Cryo-EM structure of the AA14-bound GPR101-Gs complex
    • Protein or peptide: Probable G-protein coupled receptor 101
  • Ligand: 1-(4-methylpyridin-2-yl)-3-[3-(trifluoromethyl)phenyl]thiourea
KeywordsGPCR / orphan receptor / GPR101 / constitutive activity / cryo-EM / structural protein / MEMBRANE PROTEIN
Function / homology
Function and homology information


adenylate cyclase-activating adrenergic receptor signaling pathway / G protein-coupled receptor activity / positive regulation of MAPK cascade / receptor complex / plasma membrane
Similarity search - Function
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
Probable G-protein coupled receptor 101
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsSun JP / Yu X / Gao N / Yang F / Wang JY / Yang Z / Guan Y / Wang GP
Funding support China, 5 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31725007 China
National Natural Science Foundation of China (NSFC)32130055 China
National Natural Science Foundation of China (NSFC)92057121 China
National Science Foundation (NSF, China)81825022 China
National Science Foundation (NSF, China)82225011 China
CitationJournal: Nat Chem Biol / Year: 2024
Title: Structure of GPR101-Gs enables identification of ligands with rejuvenating potential.
Authors: Zhao Yang / Jun-Yan Wang / Fan Yang / Kong-Kai Zhu / Guo-Peng Wang / Ying Guan / Shang-Lei Ning / Yan Lu / Yu Li / Chao Zhang / Yuan Zheng / Shu-Hua Zhou / Xin-Wen Wang / Ming-Wei Wang / ...Authors: Zhao Yang / Jun-Yan Wang / Fan Yang / Kong-Kai Zhu / Guo-Peng Wang / Ying Guan / Shang-Lei Ning / Yan Lu / Yu Li / Chao Zhang / Yuan Zheng / Shu-Hua Zhou / Xin-Wen Wang / Ming-Wei Wang / Peng Xiao / Fan Yi / Cheng Zhang / Peng-Ju Zhang / Fei Xu / Bao-Hua Liu / Hua Zhang / Xiao Yu / Ning Gao / Jin-Peng Sun /
Abstract: GPR101 is an orphan G protein-coupled receptor actively participating in energy homeostasis. Here we report the cryo-electron microscopy structure of GPR101 constitutively coupled to Gs heterotrimer, ...GPR101 is an orphan G protein-coupled receptor actively participating in energy homeostasis. Here we report the cryo-electron microscopy structure of GPR101 constitutively coupled to Gs heterotrimer, which reveals unique features of GPR101, including the interaction of extracellular loop 2 within the 7TM bundle, a hydrophobic chain packing-mediated activation mechanism and the structural basis of disease-related mutants. Importantly, a side pocket is identified in GPR101 that facilitates in silico screening to identify four small-molecule agonists, including AA-14. The structure of AA-14-GPR101-Gs provides direct evidence of the AA-14 binding at the side pocket. Functionally, AA-14 partially restores the functions of GH/IGF-1 axis and exhibits several rejuvenating effects in wild-type mice, which are abrogated in Gpr101-deficient mice. In summary, we provide a structural basis for the constitutive activity of GPR101. The structure-facilitated identification of GPR101 agonists and functional analysis suggest that targeting this orphan receptor has rejuvenating potential.
History
DepositionSep 4, 2023-
Header (metadata) releaseJan 3, 2024-
Map releaseJan 3, 2024-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_37358.png

Downloads & links

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Map

FileDownload / File: emd_37358.map.gz / Format: CCP4 / Size: 22.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 180 pix.
= 153. Å		0.85 Å/pix.
x 180 pix.
= 153. Å		0.85 Å/pix.
x 180 pix.
= 153. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.011
Minimum - Maximum-0.024973571 - 0.06494704
Average (Standard dev.)0.00047315308 (±0.0023648536)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions180180180
Spacing180180180
CellA=B=C: 153.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_37358_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_37358_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : Cryo-EM structure of the AA14-bound GPR101-Gs complex

EntireName: Cryo-EM structure of the AA14-bound GPR101-Gs complex
Components
  • Complex: Cryo-EM structure of the AA14-bound GPR101-Gs complex
    • Protein or peptide: Probable G-protein coupled receptor 101
  • Ligand: 1-(4-methylpyridin-2-yl)-3-[3-(trifluoromethyl)phenyl]thiourea

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Supramolecule #1: Cryo-EM structure of the AA14-bound GPR101-Gs complex

SupramoleculeName: Cryo-EM structure of the AA14-bound GPR101-Gs complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Probable G-protein coupled receptor 101

MacromoleculeName: Probable G-protein coupled receptor 101 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 56.774926 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MTSTCTNSTR ESNSSHTCMP LSKMPISLAH GIIRSTVLVI FLAASFVGNI VLALVLQRKP QLLQVTNRFI FNLLVTDLLQ ISLVAPWVV ATSVPLFWPL NSHFCTALVS LTHLFAFASV NTIVVVSVDR YLSIIHPLSY PSKMTQRRGY LLLYGTWIVA I LQSTPPLY ...String:
MTSTCTNSTR ESNSSHTCMP LSKMPISLAH GIIRSTVLVI FLAASFVGNI VLALVLQRKP QLLQVTNRFI FNLLVTDLLQ ISLVAPWVV ATSVPLFWPL NSHFCTALVS LTHLFAFASV NTIVVVSVDR YLSIIHPLSY PSKMTQRRGY LLLYGTWIVA I LQSTPPLY GWGQAAFDER NALCSMIWGA SPSYTILSVV SFIVIPLIVM IACYSVVFCA ARRQHALLYN VKRHSLEVRV KD CVENEDE EGAEKKEEFQ DESEFRRQHE GEVKAKEGRM EAKDGSLKAK EGSTGTSESS VEARGSEEVR ESSTVASDGS MEG KEGSTK VEENSMKADK GRTEVNQCSI DLGEDDMEFG EDDINFSEDD VEAVNIPESL PPSRRNSNSN PPLPRCYQCK AAKV IFIII FSYVLSLGPY CFLAVLAVWV DVETQVPQWV ITIIIWLFFL QCCIHPYVYG YMHKTIKKEI QDMLKKFFCK EKPPK EDSH PDLPGTEGGT EGKIVPSYDS ATFP

UniProtKB: Probable G-protein coupled receptor 101

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Macromolecule #2: 1-(4-methylpyridin-2-yl)-3-[3-(trifluoromethyl)phenyl]thiourea

MacromoleculeName: 1-(4-methylpyridin-2-yl)-3-[3-(trifluoromethyl)phenyl]thiourea
type: ligand / ID: 2 / Number of copies: 2 / Formula: U7D
Molecular weightTheoretical: 311.325 Da
Chemical component information

ChemComp-U7D:
1-(4-methylpyridin-2-yl)-3-[3-(trifluoromethyl)phenyl]thiourea

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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

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.2 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 3646024
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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