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- EMDB-64807: Cryo-EM structure of the GLPG1205-bound GPR84 receptor -

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Basic information

Entry
Database: EMDB / ID: EMD-64807
TitleCryo-EM structure of the GLPG1205-bound GPR84 receptor
Map dataGPR84 inactive form Cryo-EM map complex with GLPG1205
Sample
  • Complex: GLPG1205-bound GPR84 receptor complex
    • Protein or peptide: Soluble cytochrome b562
    • Protein or peptide: anti-BRIL Fab Heavy chain
    • Protein or peptide: anti-BRIL Fab Light chain
  • Protein or peptide: G-protein coupled receptor 84
  • Ligand: 9-(2-cyclopropylethynyl)-2-[[(2~{S})-1,4-dioxan-2-yl]methoxy]-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one
KeywordsGPCR / MCFA / complex / antagonist / MEMBRANE PROTEIN
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsChoi MK / Cho HS
Funding support1 items
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, 2025-
Header (metadata) releaseSep 23, 2026-
Map releaseSep 23, 2026-
UpdateSep 23, 2026-
Current statusSep 23, 2026Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_64807.png

Downloads & links

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Map

FileDownload / File: emd_64807.map.gz / Format: CCP4 / Size: 347.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationGPR84 inactive form Cryo-EM map complex with GLPG1205
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.66 Å/pix.
x 450 pix.
= 298.8 Å		0.66 Å/pix.
x 450 pix.
= 298.8 Å		0.66 Å/pix.
x 450 pix.
= 298.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.664 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0784
Minimum - Maximum-0.5807375 - 0.8166186
Average (Standard dev.)0.00018593269 (±0.0095413355)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions450450450
Spacing450450450
CellA=B=C: 298.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: GPR84 inactive form Cryo-EM map(half B) complex with GLPG1205

Fileemd_64807_half_map_1.map
AnnotationGPR84 inactive form Cryo-EM map(half B) complex with GLPG1205
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: GPR84 inactive form Cryo-EM map(half A) complex with GLPG1205

Fileemd_64807_half_map_2.map
AnnotationGPR84 inactive form Cryo-EM map(half A) complex with GLPG1205
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : GLPG1205-bound GPR84 receptor complex

EntireName: GLPG1205-bound GPR84 receptor complex
Components
  • Complex: GLPG1205-bound GPR84 receptor complex
    • Protein or peptide: Soluble cytochrome b562
    • Protein or peptide: anti-BRIL Fab Heavy chain
    • Protein or peptide: anti-BRIL Fab Light chain
  • Protein or peptide: G-protein coupled receptor 84
  • Ligand: 9-(2-cyclopropylethynyl)-2-[[(2~{S})-1,4-dioxan-2-yl]methoxy]-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one

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Supramolecule #1: GLPG1205-bound GPR84 receptor complex

SupramoleculeName: GLPG1205-bound GPR84 receptor complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 107 KDa

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Macromolecule #1: Soluble cytochrome b562

MacromoleculeName: Soluble cytochrome b562 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.885483 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
ADLEDNMETL NDNLKVIEKA DNAAQVKDAL TKMRAAALDA QKATPPKLED KSPDSPEMKD FRHGFDILVG QIDDALKLAN EGKVKEAQA AAEQLKTTRN AYHQKYLGER ARSTLQK

UniProtKB: Soluble cytochrome b562

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Macromolecule #2: anti-BRIL Fab Heavy chain

MacromoleculeName: anti-BRIL Fab Heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.769205 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
EISEVQLVES GGGLVQPGGS LRLSCAASGF NVVDFSLHWV RQAPGKGLEW VAYISSSSGS TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARWGYWPGEP WWKAFDYWGQ GTLVTVS

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Macromolecule #3: anti-BRIL Fab Light chain

MacromoleculeName: anti-BRIL Fab Light chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.025412 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQYLYYSLVT FGQGTKVEIK R

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Macromolecule #4: G-protein coupled receptor 84

MacromoleculeName: G-protein coupled receptor 84 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 43.752965 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MWNSSDANFS CYHESVLGYR YVAVSWGVVV AVTGTVGNVL TLLALAIQPK LRTRFNLLIA NLTLADLLYC TLLQPFSVDT YLHLHWRTG ATFCRVFGLL LFASNSVSIL TLCLIALGRY LLIAHPKLFP QVFSAKGIVL ALVSTWVVGV ASFAPLWPIY I LVPVVCTC ...String:
MWNSSDANFS CYHESVLGYR YVAVSWGVVV AVTGTVGNVL TLLALAIQPK LRTRFNLLIA NLTLADLLYC TLLQPFSVDT YLHLHWRTG ATFCRVFGLL LFASNSVSIL TLCLIALGRY LLIAHPKLFP QVFSAKGIVL ALVSTWVVGV ASFAPLWPIY I LVPVVCTC SFDRIRGRPY TTILMGIYFV LGLSSVGIFY CLIHRQVKRA AQALDQYKLR QASIHSNHVA RTDEAMPGRF QE LDSRLAS GGPSEGISSE PVSAATTQTL EGDSSEVGDQ INSKRAKQMA EKSPPEASAK AQPIKGARRA PDSSSEFGKV TRM CFAVFL CFALSYIPFL LLNILDARVQ APRVVHMLAA NLTWLNGCIN PVLYAAMNRQ FRQAYGSILK RGPRSFHRLH

UniProtKB: G protein-coupled receptor 84

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Macromolecule #5: 9-(2-cyclopropylethynyl)-2-[[(2~{S})-1,4-dioxan-2-yl]methoxy]-6,7...

MacromoleculeName: 9-(2-cyclopropylethynyl)-2-[[(2~{S})-1,4-dioxan-2-yl]methoxy]-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one
type: ligand / ID: 5 / Number of copies: 1 / Formula: A1L93
Molecular weightTheoretical: 378.421 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

Concentration12 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
25.0 mMTristris(hydroxymethyl)aminomethane
300.0 mMNaClsodium chloride
0.01 %LMNGlauryl maltose neopentyl glycol
0.001 %CHScholesteryl hemisuccinate
1.0 uMGLPG1205GLPG1205
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 69.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.7000000000000001 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
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: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 134250
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING
FSC plot (resolution estimation)

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