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- EMDB-39004: GLPG0974-bound human FFA2 -

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Basic information

Entry
Database: EMDB / ID: EMD-39004
TitleGLPG0974-bound human FFA2
Map data
Sample
  • Complex: GLPG0974-bound human FFA2
    • Protein or peptide: Free fatty acid receptor 2,Soluble cytochrome b562
  • Ligand: 4-[[(2~{R})-1-(1-benzothiophen-3-ylcarbonyl)-2-methyl-azetidin-2-yl]carbonyl-[(3-chlorophenyl)methyl]amino]butanoic acid
KeywordsGPCR / 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 / positive regulation of cytokine production involved in immune response / cell surface pattern recognition receptor signaling pathway / lipid storage / 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 / positive regulation of cytokine production involved in immune response / cell surface pattern recognition receptor signaling pathway / lipid storage / cellular response to fatty acid / fat cell differentiation / ligand-gated ion channel signaling pathway / negative regulation of insulin secretion / positive regulation of chemokine production / cell projection / positive regulation of interleukin-8 production / electron transport chain / G protein-coupled receptor activity / positive regulation of insulin secretion / glucose homeostasis / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / periplasmic space / electron transfer activity / G protein-coupled receptor signaling pathway / iron ion binding / lipid binding / heme binding / plasma membrane
Similarity search - Function
G protein-coupled receptor 40-related receptor / 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
Free fatty acid receptor 2 / Soluble cytochrome b562
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.36 Å
AuthorsKugawa M / Kawakami K / Kise R / Kobayashi K / Kojima A / Inoue W / Fukuda M / Inoue A / Kato HE
Funding support Japan, 2 items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)21H05142 Japan
Japan Society for the Promotion of Science (JSPS)21H04791 Japan
CitationJournal: Nat Commun / Year: 2025
Title: Structural insights into lipid chain-length selectivity and allosteric regulation of FFA2.
Authors: Mai Kugawa / Kouki Kawakami / Ryoji Kise / Carl-Mikael Suomivuori / Masaki Tsujimura / Kazuhiro Kobayashi / Asato Kojima / Wakana J Inoue / Masahiro Fukuda / Toshiki E Matsui / Ayami ...Authors: Mai Kugawa / Kouki Kawakami / Ryoji Kise / Carl-Mikael Suomivuori / Masaki Tsujimura / Kazuhiro Kobayashi / Asato Kojima / Wakana J Inoue / Masahiro Fukuda / Toshiki E Matsui / Ayami Fukunaga / Junki Koyanagi / Suhyang Kim / Hisako Ikeda / Keitaro Yamashita / Keisuke Saito / Hiroshi Ishikita / Ron O Dror / Asuka Inoue / Hideaki E Kato /
Abstract: The free fatty acid receptor 2 (FFA2) is a G protein-coupled receptor (GPCR) that selectively recognizes short-chain fatty acids to regulate metabolic and immune functions. As a promising therapeutic ...The free fatty acid receptor 2 (FFA2) is a G protein-coupled receptor (GPCR) that selectively recognizes short-chain fatty acids to regulate metabolic and immune functions. As a promising therapeutic target, FFA2 has been the focus of intensive development of synthetic ligands. However, the mechanisms by which endogenous and synthetic ligands modulate FFA2 activity remain unclear. Here, we present the structures of the human FFA2-Gi complex activated by the synthetic orthosteric agonist TUG-1375 and the positive allosteric modulator/allosteric agonist 4-CMTB, along with the structure of the inactive FFA2 bound to the antagonist GLPG0974. Structural comparisons with FFA1 and mutational studies reveal how FFA2 selects specific fatty acid chain lengths. Moreover, our structures reveal that GLPG0974 functions as an allosteric antagonist by binding adjacent to the orthosteric pocket to block agonist binding, whereas 4-CMTB binds the outer surface of transmembrane helices 6 and 7 to directly activate the receptor. Supported by computational and functional studies, these insights illuminate diverse mechanisms of ligand action, paving the way for precise GPCR-targeted drug design.
History
DepositionFeb 3, 2024-
Header (metadata) releaseApr 2, 2025-
Map releaseApr 2, 2025-
UpdateApr 9, 2025-
Current statusApr 9, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_39004.png

Downloads & links

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Map

FileDownload / File: emd_39004.map.gz / Format: CCP4 / Size: 103 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 300 pix.
= 249. Å		0.83 Å/pix.
x 300 pix.
= 249. Å		0.83 Å/pix.
x 300 pix.
= 249. Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.198
Minimum - Maximum-0.3829453 - 0.6756136
Average (Standard dev.)-0.0009127149 (±0.013455369)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 249.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_39004_half_map_1.map
Projections & Slices
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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_39004_half_map_2.map
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Sample components

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Entire : GLPG0974-bound human FFA2

EntireName: GLPG0974-bound human FFA2
Components
  • Complex: GLPG0974-bound human FFA2
    • Protein or peptide: Free fatty acid receptor 2,Soluble cytochrome b562
  • Ligand: 4-[[(2~{R})-1-(1-benzothiophen-3-ylcarbonyl)-2-methyl-azetidin-2-yl]carbonyl-[(3-chlorophenyl)methyl]amino]butanoic acid

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Supramolecule #1: GLPG0974-bound human FFA2

SupramoleculeName: GLPG0974-bound human FFA2 / 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,Soluble cytochrome b562

MacromoleculeName: Free fatty acid receptor 2,Soluble cytochrome b562 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 48.943805 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MLPDWKSSLI LMAYIIIFLT GLPANLLALR AFVGRIRQPQ PAPVHILLLS LTLADLLLLL LLPFKIIEAA SNFRWYLPKV VCALTSFGF YSSIYCSTWL LAGISIERYL GVAFPVQYKL SRRPLYGVIA ALVAWVMSFG HCTIVIIVQY LNTTEQVRSG N EITCYENF ...String:
MLPDWKSSLI LMAYIIIFLT GLPANLLALR AFVGRIRQPQ PAPVHILLLS LTLADLLLLL LLPFKIIEAA SNFRWYLPKV VCALTSFGF YSSIYCSTWL LAGISIERYL GVAFPVQYKL SRRPLYGVIA ALVAWVMSFG HCTIVIIVQY LNTTEQVRSG N EITCYENF TDNQLDVVLP VRLELCLVLF FIPMAVTIFC YWRFVWIMLS QPADLEDNWE TLNDNLKVIE KADNAAQVKD AL TKMRAAA LDAQKATPPK LEDKSPDSPE MKDFRHGFDI LVGQIDDALK LANEGKVKEA QAAAEQLKTT RNAYIQKYLL VGA QRRRRA VGLAVVTLLN FLVCFGPYNV SHLVGYHQRK SPWWRSIAVV FSSLNASLDP LLFYFSSSVV RRAFGRGLQV LRNQ GSSLL GRRGKDTAEG TNEDRGVGQG EGMPSSDFTT E

UniProtKB: Free fatty acid receptor 2, Soluble cytochrome b562, Free fatty acid receptor 2

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Macromolecule #2: 4-[[(2~{R})-1-(1-benzothiophen-3-ylcarbonyl)-2-methyl-azetidin-2-...

MacromoleculeName: 4-[[(2~{R})-1-(1-benzothiophen-3-ylcarbonyl)-2-methyl-azetidin-2-yl]carbonyl-[(3-chlorophenyl)methyl]amino]butanoic acid
type: ligand / ID: 2 / Number of copies: 1 / Formula: A1LYD
Molecular weightTheoretical: 484.995 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
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 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: 45.589 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.36 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 76538
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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