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- PDB-9m88: PGS fused GPR3 dimer with antagonist AF64394 -

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Basic information

Entry
Database: PDB / ID: 9m88
TitlePGS fused GPR3 dimer with antagonist AF64394
Components
  • GPR3
  • Glycogen synthase
KeywordsMEMBRANE PROTEIN / GPCR / dimer / antagonist
Function / homology
Function and homology information


alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity
Similarity search - Function
Glycosyl transferases group 1 / Bacterial/plant glycogen synthase / Starch synthase, catalytic domain / Starch synthase catalytic domain
Similarity search - Domain/homology
1-DODECANOL / (Z)-N-(2-hydroxyethyl)octadec-9-enamide / : / : / : / : / Glycogen synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
Pyrococcus abyssi (archaea)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsGeng, C. / Jun, X.
Funding support China, 1items
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, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Sep 24, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: GPR3
B: GPR3
C: Glycogen synthase
D: Glycogen synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)190,24626
Polymers183,2064
Non-polymers7,04022
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 2 types, 4 molecules ABCD

#1: Protein GPR3


Mass: 69747.742 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
#2: Protein Glycogen synthase


Mass: 21855.279 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Pyrococcus abyssi (archaea) / Gene: PAB2292
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
References: UniProt: Q9V2J8

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Non-polymers , 6 types, 22 molecules

#3: Chemical ChemComp-5YM / (Z)-N-(2-hydroxyethyl)octadec-9-enamide


Mass: 325.529 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H39NO2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-A1EM1 / tetracosan-1-ol / Tetracosanol


Mass: 354.653 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H50O
#5: Chemical
ChemComp-1DO / 1-DODECANOL


Mass: 186.334 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C12H26O
#6: Chemical
ChemComp-A1EM3 / [(2R)-3-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-2-decanoyloxy-propyl] dodecanoate


Mass: 551.693 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H54NO8P
#7: Chemical
ChemComp-A1EQ8 / icosan-1-ol


Mass: 298.547 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H42O
#8: Chemical ChemComp-A1EM2 / N-[(4-chloranyl-2-propan-2-yloxy-phenyl)methyl]-5-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine / AF64394


Mass: 393.869 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H20ClN5O / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: PGS fused GPR3 dimer with antagonist AF64394 / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.14 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
Buffer solutionpH: 7.5 / Details: 20mM NaCl, 100mM Hepes, 0.003% LMNG, 0.001% GDN
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 1.12 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 285367 / Symmetry type: POINT

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