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- PDB-9m8p: GPR3 dimer with antagonist AF64394 -

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Basic information

Entry
Database: PDB / ID: 9m8p
TitleGPR3 dimer with antagonist AF64394
ComponentsSoluble cytochrome b562,G-protein coupled receptor 3
KeywordsMEMBRANE PROTEIN / GPCR / dimer / antagonist
Function / homology
Function and homology information


sphingosine-1-phosphate receptor activity / regulation of meiotic nuclear division / regulation of metabolic process / electron transport chain / G protein-coupled receptor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of cold-induced thermogenesis / periplasmic space / electron transfer activity / iron ion binding ...sphingosine-1-phosphate receptor activity / regulation of meiotic nuclear division / regulation of metabolic process / electron transport chain / G protein-coupled receptor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of cold-induced thermogenesis / periplasmic space / electron transfer activity / iron ion binding / heme binding / plasma membrane / cytoplasm
Similarity search - Function
G protein-coupled receptor 3 / G protein-coupled receptor 3/6/12 orphan / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / 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
1-DODECANOL / (Z)-N-(2-hydroxyethyl)octadec-9-enamide / : / : / Soluble cytochrome b562 / G-protein coupled receptor 3
Similarity search - Component
Biological speciesEscherichia coli (E. coli)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.42 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 12, 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: Soluble cytochrome b562,G-protein coupled receptor 3
B: Soluble cytochrome b562,G-protein coupled receptor 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)103,59014
Polymers100,8932
Non-polymers2,69712
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

#1: Protein Soluble cytochrome b562,G-protein coupled receptor 3 / Cytochrome b-562 / ACCA orphan receptor


Mass: 50446.375 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (E. coli), (gene. exp.) Homo sapiens (human)
Gene: cybC, GPR3, ACCA
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
References: UniProt: P0ABE7, UniProt: P46089
#2: 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
#3: Chemical
ChemComp-1DO / 1-DODECANOL


Mass: 186.334 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C12H26O
#4: Chemical
ChemComp-A1AJD / (4Z)-oct-4-en-1-ol


Mass: 128.212 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C8H16O
#5: 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
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: GPR3 dimer with antagonist AF64394 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.1 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: 3.42 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 98600 / Symmetry type: POINT

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