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- EMDB-63702: PGS fused GPR3 dimer with antagonist AF64394 -

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Basic information

Entry
Database: EMDB / ID: EMD-63702
TitlePGS fused GPR3 dimer with antagonist AF64394
Map data
Sample
  • Complex: PGS fused GPR3 dimer with antagonist AF64394
    • Protein or peptide: GPR3
    • Protein or peptide: Glycogen synthase
  • Ligand: (Z)-N-(2-hydroxyethyl)octadec-9-enamide
  • Ligand: tetracosan-1-ol
  • Ligand: 1-DODECANOL
  • Ligand: [(2R)-3-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-2-decanoyloxy-propyl] dodecanoate
  • Ligand: icosan-1-ol
  • Ligand: N-[(4-chloranyl-2-propan-2-yloxy-phenyl)methyl]-5-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine
KeywordsGPCR / dimer / antagonist / MEMBRANE PROTEIN
Function / homologyGlycosyl transferases group 1 / Bacterial/plant glycogen synthase / Starch synthase, catalytic domain / Starch synthase catalytic domain / alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity / Glycogen synthase
Function and homology information
Biological speciesHomo sapiens (human) / Pyrococcus abyssi (archaea)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsGeng C / Jun X
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2025
Title: Mechanism and function of GPR3 regulated by a negative allosteric modulator.
Authors: Geng Chen / Jana Bláhová / Nico Staffen / Harald Hübner / Nadja Nunhöfer / Chen Qiu / Peter Gmeiner / Dorothee Weikert / Yang Du / Jun Xu /
Abstract: Allosteric modulators have gained substantial interest in current GPCR drug discovery. Here, we present a mechanism of allosteric modulation involving the dimerization of GPR3, a promising drug ...Allosteric modulators have gained substantial interest in current GPCR drug discovery. Here, we present a mechanism of allosteric modulation involving the dimerization of GPR3, a promising drug target for metabolic diseases and central nervous system disorders. We show that GPR3 forms constitutive homodimers in live cells and reveal that the inhibitor AF64394 functions as a negative allosteric modulator (NAM) specifically targeting dimeric GPR3. Using cryogenic electron microscopy (cryo-EM), we determine the structures of the AF64394-bound GPR3 dimer and its dimer-Gs signaling complex. These high-resolution structures reveal that AF64394 binds to the transmembrane dimer interface. AF64394 binding prevents the dissociation of the GPR3 dimer upon engagement with Gs and restrains transmembrane helix 5 in an inactive-like intermediate conformation, leading to reduced coupling with Gs. Our studies unveil a mechanism of dimer-specific inhibition of signaling with significant implications for the discovery of drugs targeting GPCRs capable of dimerization.
History
DepositionMar 11, 2025-
Header (metadata) releaseSep 24, 2025-
Map releaseSep 24, 2025-
UpdateOct 1, 2025-
Current statusOct 1, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_63702.png

Downloads & links

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Map

FileDownload / File: emd_63702.map.gz / Format: CCP4 / Size: 125 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 320 pix.
= 272. Å		0.85 Å/pix.
x 320 pix.
= 272. Å		0.85 Å/pix.
x 320 pix.
= 272. Å

Surface

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Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.844
Minimum - Maximum-7.1776266 - 9.916316999999999
Average (Standard dev.)-0.0011866961 (±0.16768399)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 272.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_63702_msk_1.map
Projections & Slices
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Half map: #2

Fileemd_63702_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_63702_half_map_2.map
Projections & Slices
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Sample components

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Entire : PGS fused GPR3 dimer with antagonist AF64394

EntireName: PGS fused GPR3 dimer with antagonist AF64394
Components
  • Complex: PGS fused GPR3 dimer with antagonist AF64394
    • Protein or peptide: GPR3
    • Protein or peptide: Glycogen synthase
  • Ligand: (Z)-N-(2-hydroxyethyl)octadec-9-enamide
  • Ligand: tetracosan-1-ol
  • Ligand: 1-DODECANOL
  • Ligand: [(2R)-3-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-2-decanoyloxy-propyl] dodecanoate
  • Ligand: icosan-1-ol
  • Ligand: N-[(4-chloranyl-2-propan-2-yloxy-phenyl)methyl]-5-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine

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Supramolecule #1: PGS fused GPR3 dimer with antagonist AF64394

SupramoleculeName: PGS fused GPR3 dimer with antagonist AF64394 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 140 KDa

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Macromolecule #1: GPR3

MacromoleculeName: GPR3 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 69.747742 KDa
Recombinant expressionOrganism: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
SequenceString: DYKDDDDKLE VLFQGPGSAD LEDNWETLND NLKVIEKADN AAQVKDALTK MRAAALDAQK ATPPKLEDKS PDSPEMKDFR HGFDILVGQ IDDALKLANE GKVKEAQAAA EQLKTTRNAY IQKYLMMWGA GSPLAWLSAG SGNVNVSSVG PAEGPTGPAA P LPSPKAWD ...String:
DYKDDDDKLE VLFQGPGSAD LEDNWETLND NLKVIEKADN AAQVKDALTK MRAAALDAQK ATPPKLEDKS PDSPEMKDFR HGFDILVGQ IDDALKLANE GKVKEAQAAA EQLKTTRNAY IQKYLMMWGA GSPLAWLSAG SGNVNVSSVG PAEGPTGPAA P LPSPKAWD VVLCISGTLV SCENALVVAI IVGTPAFRAP MFLLVGSLAV ADLLAGLGLV LHFAAVFCIG SAEMSLVLVG VL AMAFTAS IGSLLAITVD RYLSLYNALT YYSETTVTRT YVMLALVWGG ALGLGLLPVL AWNCLDGLTT CGVVYPLSKN HLV VLAIAF FMVFGIMLQL YAQICRIVCG IDCSFWNESY LTGSRDERKK SLLSKFGMDE GVTFMFIGRF DRGQKGVDVL LKAI EILSS KKEFQEMRFI IIGKGDPELE GWARSLEEKH GNVKVITEML SREFVRELYG SVDFVIIPSY FEPFGLVALE AMCLG AIPI ASAVGGLRDI ITNETGILVK AGDPGELANA ILKALELSRS DLSKFRENCK KRAMSFSRKG IATLAVVLGA FAACWL PFT VYCLLGDAHS PPLYTYLTLL PATYNSMINP IIYAFRNQDV QKVLWAVCCC CSSSKIPFRS RSPSDVLEHH HHHHHHH

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Macromolecule #2: Glycogen synthase

MacromoleculeName: Glycogen synthase / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Pyrococcus abyssi (archaea)
Molecular weightTheoretical: 21.855279 KDa
Recombinant expressionOrganism: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
SequenceString: GIDCSFWNES YLTGSRDERK KSLLSKFGMD EGVTFMFIGR FDRGQKGVDV LLKAIEILSS KKEFQEMRFI IIGKGDPELE GWARSLEEK HGNVKVITEM LSREFVRELY GSVDFVIIPS YFEPFGLVAL EAMCLGAIPI ASAVGGLRDI ITNETGILVK A GDPGELAN ...String:
GIDCSFWNES YLTGSRDERK KSLLSKFGMD EGVTFMFIGR FDRGQKGVDV LLKAIEILSS KKEFQEMRFI IIGKGDPELE GWARSLEEK HGNVKVITEM LSREFVRELY GSVDFVIIPS YFEPFGLVAL EAMCLGAIPI ASAVGGLRDI ITNETGILVK A GDPGELAN AILKALELSR SDLSKFRENC KKRAMSFS

UniProtKB: Glycogen synthase

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Macromolecule #3: (Z)-N-(2-hydroxyethyl)octadec-9-enamide

MacromoleculeName: (Z)-N-(2-hydroxyethyl)octadec-9-enamide / type: ligand / ID: 3 / Number of copies: 2 / Formula: 5YM
Molecular weightTheoretical: 325.529 Da
Chemical component information

ChemComp-5YM:
(Z)-N-(2-hydroxyethyl)octadec-9-enamide

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Macromolecule #4: tetracosan-1-ol

MacromoleculeName: tetracosan-1-ol / type: ligand / ID: 4 / Number of copies: 2 / Formula: A1EM1
Molecular weightTheoretical: 354.653 Da

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Macromolecule #5: 1-DODECANOL

MacromoleculeName: 1-DODECANOL / type: ligand / ID: 5 / Number of copies: 8 / Formula: 1DO
Molecular weightTheoretical: 186.334 Da
Chemical component information

ChemComp-1DO:
1-DODECANOL

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Macromolecule #6: [(2R)-3-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-2-decanoyloxy-pro...

MacromoleculeName: [(2R)-3-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-2-decanoyloxy-propyl] dodecanoate
type: ligand / ID: 6 / Number of copies: 4 / Formula: A1EM3
Molecular weightTheoretical: 551.693 Da

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Macromolecule #7: icosan-1-ol

MacromoleculeName: icosan-1-ol / type: ligand / ID: 7 / Number of copies: 4 / Formula: A1EQ8
Molecular weightTheoretical: 298.547 Da

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Macromolecule #8: N-[(4-chloranyl-2-propan-2-yloxy-phenyl)methyl]-5-phenyl-[1,2,4]t...

MacromoleculeName: N-[(4-chloranyl-2-propan-2-yloxy-phenyl)methyl]-5-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine
type: ligand / ID: 8 / Number of copies: 2 / Formula: A1EM2
Molecular weightTheoretical: 393.869 Da

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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 / Details: 20mM NaCl, 100mM Hepes, 0.003% LMNG, 0.001% GDN
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 1.12 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

8x2k

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 285367
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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