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- EMDB-47950: Cryo-EM structure of the ONO2550289-bound prostaglandin D2 recept... -

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Basic information

Entry
Database: EMDB / ID: EMD-47950
TitleCryo-EM structure of the ONO2550289-bound prostaglandin D2 receptor (DP1)-bRIL-Fab complex
Map datastructure of the ONO2550289-bound prostaglandin D2 receptor (DP1)-bRIL-Fab complex
Sample
  • Complex: ONO2550289 bound to DP1bRIL-BAG2Fab-Nb complex
    • Protein or peptide: anti-BRIL Fab Heavy Chain
    • Protein or peptide: anti-Fab Nanobody synthetic construct
    • Protein or peptide: anti-BRIL Fab Light Chain
    • Protein or peptide: Prostaglandin D2 receptor,Soluble cytochrome b562
  • Ligand: [2-chloro-5-(2,6-dimethyl-4-{[(2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl]methoxy}benzamido)phenyl]acetic acid
KeywordsGPCR / cryo-EM / DP1 / inverse agonist / ONO2550289 / prostaglandin D2 receptor / prostanoid DP receptor / PGD receptor / PTGDR / DP1-bRIL chimera / MEMBRANE PROTEIN / MEMBRANE PROTEIN-Immune System complex
Function / homology
Function and homology information


prostaglandin J receptor activity / prostaglandin D receptor activity / adenosine metabolic process / Prostanoid ligand receptors / cellular response to prostaglandin D stimulus / male sex determination / sleep / mast cell degranulation / electron transport chain / positive regulation of cytosolic calcium ion concentration ...prostaglandin J receptor activity / prostaglandin D receptor activity / adenosine metabolic process / Prostanoid ligand receptors / cellular response to prostaglandin D stimulus / male sex determination / sleep / mast cell degranulation / electron transport chain / positive regulation of cytosolic calcium ion concentration / G alpha (s) signalling events / periplasmic space / electron transfer activity / G protein-coupled receptor signaling pathway / iron ion binding / inflammatory response / heme binding / membrane / plasma membrane
Similarity search - Function
Prostaglandin D receptor / Prostanoid receptor / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / 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
Soluble cytochrome b562 / Prostaglandin D2 receptor
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.89 Å
AuthorsDavoudinasab B / Cherezov V / Han GW
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM127086 United States
CitationJournal: Nat Commun / Year: 2025
Title: Structural insights into the mechanism of activation and inhibition of the prostaglandin D2 receptor 1.
Authors: Behnaz Davoudinasab / Aleksey Raskovalov / Woojin Lee / Donggyun Kim / Heesoo Kim / Jordy Homing Lam / Gye Won Han / Vsevolod Katritch / Vadim Cherezov /
Abstract: The prostaglandin D2 receptor 1 (DP1), a member of the prostanoid G protein-coupled receptor (GPCR) family, plays critical roles in allergic responses, sleep regulation, immune modulation, and ...The prostaglandin D2 receptor 1 (DP1), a member of the prostanoid G protein-coupled receptor (GPCR) family, plays critical roles in allergic responses, sleep regulation, immune modulation, and vasodilation. Here, we present five high-resolution cryo-electron microscopy (cryo-EM) structures of the human DP1 receptor, including an apo structure, two inactive state structures bound to two different inverse agonists developed by ONO Pharmaceutical, and two active state structures in complex with the G protein and bound to the endogenous agonist PGD2 and its selective derivative BW245C. Structural analysis, complemented by molecular dynamics simulations and site-directed mutagenesis, reveals key residues involved in ligand recognition and suggests a distinct activation mechanism for DP1, which lacks most of the conserved class A GPCR motifs. Notably, the unique residue K76 within the conserved sodium pocket acts as a major activation switch, while amphiphilic helix 8 adopts an unconventional orientation essential for receptor function. These findings offer valuable insights into the structure and function of prostanoid receptors and may facilitate the development of therapeutics targeting DP1.
History
DepositionNov 18, 2024-
Header (metadata) releaseSep 3, 2025-
Map releaseSep 3, 2025-
UpdateOct 22, 2025-
Current statusOct 22, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47950.png

Downloads & links

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Map

FileDownload / File: emd_47950.map.gz / Format: CCP4 / Size: 144.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationstructure of the ONO2550289-bound prostaglandin D2 receptor (DP1)-bRIL-Fab complex
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 336 pix.
= 288.96 Å		0.86 Å/pix.
x 336 pix.
= 288.96 Å		0.86 Å/pix.
x 336 pix.
= 288.96 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.86 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 7.7
Minimum - Maximum-63.480953 - 85.394090000000006
Average (Standard dev.)-0.0080602905 (±1.2676426)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions336336336
Spacing336336336
CellA=B=C: 288.96 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map B

Fileemd_47950_half_map_1.map
AnnotationHalf Map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map A

Fileemd_47950_half_map_2.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : ONO2550289 bound to DP1bRIL-BAG2Fab-Nb complex

EntireName: ONO2550289 bound to DP1bRIL-BAG2Fab-Nb complex
Components
  • Complex: ONO2550289 bound to DP1bRIL-BAG2Fab-Nb complex
    • Protein or peptide: anti-BRIL Fab Heavy Chain
    • Protein or peptide: anti-Fab Nanobody synthetic construct
    • Protein or peptide: anti-BRIL Fab Light Chain
    • Protein or peptide: Prostaglandin D2 receptor,Soluble cytochrome b562
  • Ligand: [2-chloro-5-(2,6-dimethyl-4-{[(2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl]methoxy}benzamido)phenyl]acetic acid

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Supramolecule #1: ONO2550289 bound to DP1bRIL-BAG2Fab-Nb complex

SupramoleculeName: ONO2550289 bound to DP1bRIL-BAG2Fab-Nb complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: anti-BRIL Fab Heavy Chain

MacromoleculeName: anti-BRIL Fab Heavy Chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 24.321084 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: EISEVQLVES GGGLVQPGGS LRLSCAASGF NVVDFSLHWV RQAPGKGLEW VAYISSSSGS TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARWGYWPGEP WWKAFDYWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY F PEPVTVSW ...String:
EISEVQLVES GGGLVQPGGS LRLSCAASGF NVVDFSLHWV RQAPGKGLEW VAYISSSSGS TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARWGYWPGEP WWKAFDYWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY F PEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKKVEPK S

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Macromolecule #2: anti-Fab Nanobody synthetic construct

MacromoleculeName: anti-Fab Nanobody synthetic construct / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 13.390644 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GSQVQLQESG GGLVQPGGSL RLSCAASGRT ISRYAMSWFR QAPGKEREFV AVARRSGDGA FYADSVQGRF TVSRDDAKNT VYLQMNSLK PEDTAVYYCA IDSDTFYSGS YDYWGQGTQV TVSS

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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: synthetic construct (others)
Molecular weightTheoretical: 23.353947 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQYLYYSLVT FGQGTKVEIK RTVAAPSVFI FPPSDSQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG N SQESVTEQ ...String:
SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQYLYYSLVT FGQGTKVEIK RTVAAPSVFI FPPSDSQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG N SQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV THQGLSSPVT KSFNRG

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Macromolecule #4: Prostaglandin D2 receptor,Soluble cytochrome b562

MacromoleculeName: Prostaglandin D2 receptor,Soluble cytochrome b562 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 55.687906 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFADYKD DDDGAPMKSP FYRCQNTTSV EKGNSAVMGG VLFSTGLLGN LLALGLLARS GLGWCSRRPL RPLPSVFYM LVCGLTVTDL LGKCLLSPVV LAAYAQNRSL RVLAPALDNS LCQAFAFFMS FFGLSSTLQL LAMALERWLS L GHPFFYRR ...String:
MKTIIALSYI FCLVFADYKD DDDGAPMKSP FYRCQNTTSV EKGNSAVMGG VLFSTGLLGN LLALGLLARS GLGWCSRRPL RPLPSVFYM LVCGLTVTDL LGKCLLSPVV LAAYAQNRSL RVLAPALDNS LCQAFAFFMS FFGLSSTLQL LAMALERWLS L GHPFFYRR HITLRLGALV APVVSAFSLA FCALPFMGFG KFVQYCPGTW CFIQMVHEEG SLSVLGYSVL YSSLMALLVL AT VLCNLGA MRNLYAMHRR LQADLEDNWE TLNDNLKVIE KADNAAQVKD ALTKMRAAAL DAQKATPPKL EDKSPDSPEM KDF RHGFDI LVGQIDDALK LANEGKVKEA QAAAEQLKTT RNAYIQKYLE RARSTLLEEL DALLLLALMT VLFTMCSLPV IYRA YYGAF KDVKEKNRTS EEAEDLRALR FLSVISIVNP WIFIIFRSPV FRIFFHKIFI RPLRYRSRCS NSTNMESSLG RPLEV LFQG PHHHHHHHHH H

UniProtKB: Prostaglandin D2 receptor, Soluble cytochrome b562, Prostaglandin D2 receptor

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Macromolecule #5: [2-chloro-5-(2,6-dimethyl-4-{[(2S)-4-methyl-3,4-dihydro-2H-1,4-be...

MacromoleculeName: [2-chloro-5-(2,6-dimethyl-4-{[(2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl]methoxy}benzamido)phenyl]acetic acid
type: ligand / ID: 5 / Number of copies: 1 / Formula: A1BIL
Molecular weightTheoretical: 494.967 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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 65.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 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:

6ww2


Details: DP1: AlphaFold2
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.89 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.7.0) / Number images used: 415106
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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