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- EMDB-67995: Cryo-EM structure of Free fatty acid receptor 2 (FFA2)-ARK1 with ... -

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Basic information

Entry
Database: EMDB / ID: EMD-67995
TitleCryo-EM structure of Free fatty acid receptor 2 (FFA2)-ARK1 with GLPG0974
Map data
Sample
  • Complex: Cryo-EM structure of Free fatty acid receptor 2 (FFA2)-ARK1 with GLPG0974
    • Protein or peptide: Free fatty acid receptor 2,human free fatty acid receptor 2 (FFA2) fused with de novo designed ARK1
  • Ligand: GLPG-0974
  • Ligand: water
KeywordsGPCR / FFA2 / Free fatty acid receptor 2 / GLPG0974 / ARK1 / MEMBRANE PROTEIN
Function / homology
Function and homology information


positive regulation of acute inflammatory response to non-antigenic stimulus / regulation of peptide hormone secretion / regulation of acute inflammatory response / leukocyte chemotaxis involved in inflammatory response / mucosal immune response / Free fatty acid receptors / lipid storage / cell surface pattern recognition receptor signaling pathway / positive regulation of cytokine production involved in immune response / cellular response to fatty acid ...positive regulation of acute inflammatory response to non-antigenic stimulus / regulation of peptide hormone secretion / regulation of acute inflammatory response / leukocyte chemotaxis involved in inflammatory response / mucosal immune response / Free fatty acid receptors / lipid storage / cell surface pattern recognition receptor signaling pathway / positive regulation of cytokine production involved in immune response / cellular response to fatty acid / fat cell differentiation / positive regulation of chemokine production / cell projection / positive regulation of interleukin-8 production / G protein-coupled receptor activity / phospholipase C-activating G protein-coupled receptor signaling pathway / glucose homeostasis / G alpha (q) signalling events / G protein-coupled receptor signaling pathway / lipid binding / plasma membrane
Similarity search - Function
G protein-coupled receptor 40-related receptor / G-protein coupled receptors family 1 signature. / 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
Free fatty acid receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / Resolution: 2.93 Å
AuthorsKojima A / Kawakami K / Narita T / Kugawa M / Hayashi K / Fukuda M / Kato HE
Funding support Japan, 6 items
OrganizationGrant numberCountry
Japan Science and TechnologyJPMJAX222F Japan
Japan Science and TechnologyJPMJPR24OF Japan
Japan Society for the Promotion of Science (JSPS)25K09525 Japan
Japan Society for the Promotion of Science (JSPS)24H02262 Japan
Japan Society for the Promotion of Science (JSPS)25H01338 Japan
Japan Society for the Promotion of Science (JSPS)JP24KJ0981 Japan
CitationJournal: Nat Struct Mol Biol / Year: 2026
Title: Universal pipeline for high-resolution GPCR structure determination.
Authors: Asato Kojima / Kouki Kawakami / Naoya Kobayashi / Kazuhiro Kobayashi / Toshiki E Matsui / Kohei Uemoto / Yuzhong Gu / Tomohiro J Narita / Mai Kugawa / Masahiro Fukuda / Hideaki E Kato /
Abstract: G protein-coupled receptors (GPCRs) regulate human physiology and are major drug targets. Although cryo-electron microscopy has accelerated GPCR structural biology, inactive-state structures remain ...G protein-coupled receptors (GPCRs) regulate human physiology and are major drug targets. Although cryo-electron microscopy has accelerated GPCR structural biology, inactive-state structures remain difficult because current fusion-based strategies often require extensive experimental screening to identify rigid constructs suitable for high-resolution reconstruction. Here we introduce a universal pipeline that integrates an in silico fusion construct screening program, NOAH (nonexperimental, artificial-intelligence-assisted, high-throughput construct screening for structural analysis), with a de novo designed fusion protein, ARK1 (artificially designed fiducial marker). NOAH enabled structure determination of vasopressin V2 receptor bound to the antagonist tolvaptan or partial agonist OPC51803 and bradykinin B2 receptor bound to the antagonist icatibant, revealing receptor activation and inhibition mechanisms. Coupling NOAH to ARK1 improved the V2 receptor-tolvaptan map and enabled high-resolution structures of lysophosphatidic acid receptor 2 bound to Ki16425 and free fatty acid receptor 2 bound to GLPG0974. NOAH-ARK1 minimizes trial-and-error construct optimization and provides a broadly applicable route for GPCR structural analysis and drug discovery.
History
DepositionDec 26, 2025-
Header (metadata) releaseSep 9, 2026-
Map releaseSep 9, 2026-
UpdateSep 9, 2026-
Current statusSep 9, 2026Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_67995.png

Downloads & links

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Map

FileDownload / File: emd_67995.map.gz / Format: CCP4 / Size: 32.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 204 pix.
= 169.32 Å		0.83 Å/pix.
x 204 pix.
= 169.32 Å		0.83 Å/pix.
x 204 pix.
= 169.32 Å

Surface

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.12
Minimum - Maximum-0.30455226 - 0.5784398
Average (Standard dev.)-0.0009617296 (±0.022897756)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin484848
Dimensions204204204
Spacing204204204
CellA=B=C: 169.31999 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_67995_msk_1.map
Projections & Slices
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Half map: #2

Fileemd_67995_half_map_1.map
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Half map: #1

Fileemd_67995_half_map_2.map
Projections & Slices
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Sample components

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Entire : Cryo-EM structure of Free fatty acid receptor 2 (FFA2)-ARK1 with ...

EntireName: Cryo-EM structure of Free fatty acid receptor 2 (FFA2)-ARK1 with GLPG0974
Components
  • Complex: Cryo-EM structure of Free fatty acid receptor 2 (FFA2)-ARK1 with GLPG0974
    • Protein or peptide: Free fatty acid receptor 2,human free fatty acid receptor 2 (FFA2) fused with de novo designed ARK1
  • Ligand: GLPG-0974
  • Ligand: water

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Supramolecule #1: Cryo-EM structure of Free fatty acid receptor 2 (FFA2)-ARK1 with ...

SupramoleculeName: Cryo-EM structure of Free fatty acid receptor 2 (FFA2)-ARK1 with GLPG0974
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Free fatty acid receptor 2,human free fatty acid receptor 2 (FFA2...

MacromoleculeName: Free fatty acid receptor 2,human free fatty acid receptor 2 (FFA2) fused with de novo designed ARK1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 85.565453 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MKTIIALSYI FCLVFADYKD DDDAENLYFQ GMLPDWKSSL ILMAYIIIFL TGLPANLLAL RAFVGRIRQP QPAPVHILLL SLTLADLLL LLLLPFKIIE AASNFRWYLP KVVCALTSFG FYSSIYCSTW LLAGISIERY LGVAFPVQYK LSRRPLYGVI A ALVAWVMS ...String:
MKTIIALSYI FCLVFADYKD DDDAENLYFQ GMLPDWKSSL ILMAYIIIFL TGLPANLLAL RAFVGRIRQP QPAPVHILLL SLTLADLLL LLLLPFKIIE AASNFRWYLP KVVCALTSFG FYSSIYCSTW LLAGISIERY LGVAFPVQYK LSRRPLYGVI A ALVAWVMS FGHCTIVIIV QYLNTTEQVR SGNEITCYEN FTDNQLDVVL PVRLELCLVL FFIPMAVTIF CYWRFVWIML SH LELRRLL REQGEKLLKL AEESEKKIKE AIEKGEDVVK VATEETHKLI KAIWESSFEV ARLLGVPEEV LEKFRKELEK LLE ESKKRI EEAIKKGEDV LKVVEEEAKK LREHSEKFLE TARSLGVDPR PLERLARIVR VVEESLVRIV KAIKEGEDVE KVLL SESTL IKSSIILSSG LDPREAYEEL LATYEETRDS ELVKEFVELV RELLRLRGEP EELVRQLDKL IEAIDRMEKA VAEGE DTLP LFLELAREIL KALSDVARIL AEREGLDVEL IDEIVDTASR LLEEVIKKAK EGEDLDEEEE KVKKELEELK KRTEER ARA LGQDVELVRT IVDSLSTLLS EIVEGIKRVK EGEDPLEVLA RVVLTATLQI LELVRTAERR RRERRRRRAV GLAVVTL LN FLVCFGPYNV SHLVGYHQRK SPWWRSIAVV FSSLNASLDP LLFYFSSSVV RRAFGRGLQV LRNQGSSLLG RRGKDTAE G TNEDRGVGQG EGMPSSDFTT ELEVLFQ

UniProtKB: Free fatty acid receptor 2, Free fatty acid receptor 2

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Macromolecule #2: GLPG-0974

MacromoleculeName: GLPG-0974 / type: ligand / ID: 2 / Number of copies: 1 / Formula: A1LYD
Molecular weightTheoretical: 484.995 Da

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Macromolecule #3: water

MacromoleculeName: water / type: ligand / ID: 3 / Number of copies: 7 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 49.3 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.8 µm
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: INSILICO MODEL / In silico model: AlphaFold
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.93 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 196932
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
Output model

PDB-21ty:
Cryo-EM structure of Free fatty acid receptor 2 (FFA2)-ARK1 with GLPG0974

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