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- PDB-9v6t: Cryo-EM structure of the GLPG1205-bound GPR84 receptor -

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Basic information

Entry
Database: PDB / ID: 9v6t
TitleCryo-EM structure of the GLPG1205-bound GPR84 receptor
Components
  • G-protein coupled receptor 84
  • Soluble cytochrome b562
  • anti-BRIL Fab Heavy chain
  • anti-BRIL Fab Light chain
KeywordsMEMBRANE PROTEIN / GPCR / MCFA / complex / antagonist
Function / homology
Function and homology information


urotensin II receptor activity / tertiary granule membrane / specific granule membrane / neuropeptide signaling pathway / electron transport chain / G alpha (s) signalling events / electron transfer activity / signaling receptor complex / periplasmic space / iron ion binding ...urotensin II receptor activity / tertiary granule membrane / specific granule membrane / neuropeptide signaling pathway / electron transport chain / G alpha (s) signalling events / electron transfer activity / signaling receptor complex / periplasmic space / iron ion binding / heme binding / Neutrophil degranulation / plasma membrane
Similarity search - Function
Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile.
Similarity search - Domain/homology
: / Soluble cytochrome b562 / G protein-coupled receptor 84
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsChoi, M.K. / Cho, H.S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Exp Mol Med / Year: 2026
Title: Pharmacological modulation of GPR84 revealed by dual states structures and immune functional assays.
Authors: Myung Kyung Choi / Dong Jin Park / Pankyung Kim / Hee Seong Choi / Sorin Myung / Youngki Yoo / Nienping Chang / Ga-Yeon Yoon / Hye Jin Kang / Sang-Jun Ha / Hyun-Soo Cho /
Abstract: G-protein-coupled receptor 84 (GPR84) is an orphan class A GPCR selectively activated by medium chain fatty acids and highly expressed in immune cells, where it modulates pro-inflammatory signaling. ...G-protein-coupled receptor 84 (GPR84) is an orphan class A GPCR selectively activated by medium chain fatty acids and highly expressed in immune cells, where it modulates pro-inflammatory signaling. The structural basis of GPR84 inactivation and antagonism has remained unclear, limiting the rational design of pathway-selective modulators despite its clinical relevance in metabolic inflammation and fibrotic diseases. Here, we report cryo-electron microscopy structures of human GPR84 in inactive and active states. The 3.5 Å inactive structure bound to the antagonist GLPG1205 reveals a lid-like conformation of extracellular loop 2 and an inward reorientation of Arg172, with the antagonist head group blocking the allosteric sodium-binding site. Molecular dynamics simulations further support these findings, identifying an aberrant TM5, TM6 lateral entry gate. By contrast, the 3.17 Å agonist ZQ-16, Gαi complex, shows a rearranged toggle switch and comparative analyses highlight extracellular loop 2 conformational plasticity. Immune functional assays in THP-1 cells demonstrated that ZQ-16 elicited GPR84-dependent activation and cytokine production, which were effectively abrogated by GLPG1205. Mutagenesis combined with functional assays validates key ligand interactions, providing a framework for the rational design of pathway selective GPR84 modulators.
History
DepositionMay 27, 2025Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 23, 2026Provider: repository / Type: Initial release
Revision 1.0Sep 23, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Soluble cytochrome b562
H: anti-BRIL Fab Heavy chain
L: anti-BRIL Fab Light chain
R: G-protein coupled receptor 84
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,8115
Polymers82,4334
Non-polymers3781
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, electron density map, gel filtration, SEC profile size
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Soluble cytochrome b562 / Cytochrome b-562


Mass: 12885.483 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: cybC / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P0ABE7
#2: Antibody anti-BRIL Fab Heavy chain


Mass: 13769.205 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GPR84, EX33 / Production host: Spodoptera frugiperda (fall armyworm)
#3: Antibody anti-BRIL Fab Light chain


Mass: 12025.412 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#4: Protein G-protein coupled receptor 84 / Inflammation-related G-protein coupled receptor EX33


Mass: 43752.965 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GPR84, EX33 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9NQS5
#5: Chemical ChemComp-A1L93 / 9-(2-cyclopropylethynyl)-2-[[(2~{S})-1,4-dioxan-2-yl]methoxy]-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one


Mass: 378.421 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H22N2O4 / 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: GLPG1205-bound GPR84 receptor complex / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.107 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
125 mMtris(hydroxymethyl)aminomethaneTris1
2300 mMsodium chlorideNaCl1
30.01 %lauryl maltose neopentyl glycolLMNG1
40.001 %cholesteryl hemisuccinateCHS1
51 uMGLPG1205GLPG12051
SpecimenConc.: 12 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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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: 700 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 69 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 134250 / Symmetry type: POINT

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