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- EMDB-28185: Structure of FFAR1-Gq complex bound to TAK-875 in a lipid nanodisc -

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Entry
Database: EMDB / ID: EMD-28185
TitleStructure of FFAR1-Gq complex bound to TAK-875 in a lipid nanodisc
Map data
Sample
  • Complex: Free Fatty Acid Receptor1- G-Protein complex
    • Protein or peptide: A modified Guanine nucleotide-binding protein G(q) subunit alpha
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: scFv16
    • Protein or peptide: Free fatty acid receptor 1
  • Ligand: [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid
KeywordsFFAR1 / FFAs / diabetes / CryoEM / MEMBRANE PROTEIN
Function / homology
Function and homology information


bioactive lipid receptor activity / Free fatty acid receptors / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / response to fatty acid / positive regulation of calcium ion transport / insulin secretion / negative regulation of interleukin-1 beta production / ligand-gated ion channel signaling pathway / G protein-coupled receptor activity ...bioactive lipid receptor activity / Free fatty acid receptors / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / response to fatty acid / positive regulation of calcium ion transport / insulin secretion / negative regulation of interleukin-1 beta production / ligand-gated ion channel signaling pathway / G protein-coupled receptor activity / positive regulation of insulin secretion / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / glucose homeostasis / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / positive regulation of cytosolic calcium ion concentration / GTPase binding / Ca2+ pathway / fibroblast proliferation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / lipid binding / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
GPR40 receptor fatty acid / G protein-coupled receptor 40-related receptor / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein ...GPR40 receptor fatty acid / G protein-coupled receptor 40-related receptor / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Free fatty acid receptor 1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsKumari P / Inoue A / Chapman K / Lian P / Rosenbaum DM
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM116387 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2023
Title: Molecular mechanism of fatty acid activation of FFAR1.
Authors: Punita Kumari / Asuka Inoue / Karen Chapman / Peng Lian / Daniel M Rosenbaum /
Abstract: FFAR1 is a G-protein-coupled receptor (GPCR) that responds to circulating free fatty acids to enhance glucose-stimulated insulin secretion and release of incretin hormones. Due to the glucose- ...FFAR1 is a G-protein-coupled receptor (GPCR) that responds to circulating free fatty acids to enhance glucose-stimulated insulin secretion and release of incretin hormones. Due to the glucose-lowering effect of FFAR1 activation, potent agonists for this receptor have been developed for the treatment of diabetes. Previous structural and biochemical studies of FFAR1 showed multiple sites of ligand binding to the inactive state but left the mechanism of fatty acid interaction and receptor activation unknown. We used cryo-electron microscopy to elucidate structures of activated FFAR1 bound to a G mimetic, which were induced either by the endogenous FFA ligand docosahexaenoic acid or γ-linolenic acid and the agonist drug TAK-875. Our data identify the orthosteric pocket for fatty acids and show how both endogenous hormones and synthetic agonists induce changes in helical packing along the outside of the receptor that propagate to exposure of the G-protein-coupling site. These structures show how FFAR1 functions without the highly conserved "DRY" and "NPXXY" motifs of class A GPCRs and also illustrate how the orthosteric site of a receptor can be bypassed by membrane-embedded drugs to confer full activation of G protein signaling.
History
DepositionSep 17, 2022-
Header (metadata) releaseMay 24, 2023-
Map releaseMay 24, 2023-
UpdateOct 30, 2024-
Current statusOct 30, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28185.png

Downloads & links

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Map

FileDownload / File: emd_28185.map.gz / Format: CCP4 / Size: 35.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 210 pix.
= 224.7 Å		1.07 Å/pix.
x 210 pix.
= 224.7 Å		1.07 Å/pix.
x 210 pix.
= 224.7 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.07 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0212
Minimum - Maximum-0.062438417 - 0.11956589
Average (Standard dev.)0.000108243425 (±0.0040261257)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions210210210
Spacing210210210
CellA=B=C: 224.70001 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_28185_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_28185_half_map_2.map
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Sample components

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Entire : Free Fatty Acid Receptor1- G-Protein complex

EntireName: Free Fatty Acid Receptor1- G-Protein complex
Components
  • Complex: Free Fatty Acid Receptor1- G-Protein complex
    • Protein or peptide: A modified Guanine nucleotide-binding protein G(q) subunit alpha
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: scFv16
    • Protein or peptide: Free fatty acid receptor 1
  • Ligand: [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid

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Supramolecule #1: Free Fatty Acid Receptor1- G-Protein complex

SupramoleculeName: Free Fatty Acid Receptor1- G-Protein complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: A modified Guanine nucleotide-binding protein G(q) subunit alpha

MacromoleculeName: A modified Guanine nucleotide-binding protein G(q) subunit alpha
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 27.638461 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGSTLSAEDK AAVERSKMID RNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHTSG IFETKFQVDK VNFHMFDVGG QRDERRKWI QCFNDVTAII FVVDSSDYNR LQEALNDFKS IWNNRWLRTI SVILFLNKQD LLAEKVLAGK SKIEDYFPEF A RYTTPEDA ...String:
MGSTLSAEDK AAVERSKMID RNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHTSG IFETKFQVDK VNFHMFDVGG QRDERRKWI QCFNDVTAII FVVDSSDYNR LQEALNDFKS IWNNRWLRTI SVILFLNKQD LLAEKVLAGK SKIEDYFPEF A RYTTPEDA TPEPGEDPRV TRAKYFIRKE FVDISTASGD GRHICYPHFT CAVDTENARR IFNDCKDIIL QMNLREYNLV

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Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.41693 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL ...String:
MSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD INAICFFPNG NA FATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAGHDNRVSC LGV TDDGMA VATGSWDSFL KIWN

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 9.137474 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MGHHHHHHHH GGASNNTASI AQARKLVEQL KMEANIDRIK VSKAAADLMA YCEAHAKEDP LLTPVPASEN PFREKKFFCA IL

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #4: scFv16

MacromoleculeName: scFv16 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 34.930852 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKFLVNVALV FMVVYISYIY ADSYYHHHHH HHHHHDYDIP TTENLYFQGA MGDVQLVESG GGLVQPGGSR KLSCSASGFA FSSFGMHWV RQAPEKGLEW VAYISSGSGT IYYADTVKGR FTISRDDPKN TLFLQMTSLR SEDTAMYYCV RSIYYYGSSP F DFWGQGTT ...String:
MKFLVNVALV FMVVYISYIY ADSYYHHHHH HHHHHDYDIP TTENLYFQGA MGDVQLVESG GGLVQPGGSR KLSCSASGFA FSSFGMHWV RQAPEKGLEW VAYISSGSGT IYYADTVKGR FTISRDDPKN TLFLQMTSLR SEDTAMYYCV RSIYYYGSSP F DFWGQGTT LTVSSGGGGS GGGGSGGGGS DIVMTQATSS VPVTPGESVS ISCRSSKSLL HSNGNTYLYW FLQRPGQSPQ LL IYRMSNL ASGVPDRFSG SGSGTAFTLT ISRLEAEDVG VYYCMQHLEY PLTFGAGTKL ELKAAAENLY FQGHHHHHHH H

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Macromolecule #5: Free fatty acid receptor 1

MacromoleculeName: Free fatty acid receptor 1 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 54.298785 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGKTIIALSY IFCLVFADYK DDDDAENLYF QGNIFEMLRI DEGLRLKIYK DTEGYYTIGI GHLLTKSPSL NAAKSELDKA IGRNTNGVI TKDEAEKLFN QDVDAAVRGI LRNAKLKPVY DSLDAVRRAA LINMVFQMGE TGVAGFTNSL RMLQQKRWDE A AVNLAKSR ...String:
MGKTIIALSY IFCLVFADYK DDDDAENLYF QGNIFEMLRI DEGLRLKIYK DTEGYYTIGI GHLLTKSPSL NAAKSELDKA IGRNTNGVI TKDEAEKLFN QDVDAAVRGI LRNAKLKPVY DSLDAVRRAA LINMVFQMGE TGVAGFTNSL RMLQQKRWDE A AVNLAKSR WYNQTPNRAK RVITTFRTGT WDAYLEVLFQ GPEFDLPPQL SFGLYVAAFA LGFPLNVLAI RGATAHARLR LT PSLVYAL NLGCSDLLLT VSLPLKAVEA LASGAWPLPA SLCPVFAVAH FFPLYAGGGF LAALSAGRYL GAAFPLGYQA FRR PCYSWG VCAAIWALVL CHLGLVFGLE APGGWLDHSN TSLGINTPVN GSPVCLEAWD PASAGPARFS LSLLLFFLPL AITA FCYVG CLRALARSGL THRRKLRAAW VAGGALLTLL LCVGPYNASN VASFLYPNLG GSWRKLGLIT GAWSVVLNPL VTGYL GRGP GLKTVCAART QGGKSQK

UniProtKB: Free fatty acid receptor 1

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Macromolecule #6: [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3...

MacromoleculeName: [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid
type: ligand / ID: 6 / Number of copies: 1 / Formula: 2YB
Molecular weightTheoretical: 524.625 Da
Chemical component information

ChemComp-2YB:
[(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid

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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

Concentration5 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
20.0 mMHEPES
0.004 %glyco-diosgenin
0.0004 %cholestoryl hemisuccinate
0.5 mMTris (2-carboxyethyl) phosphine
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 1.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.4000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 7367115
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 108950
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION (ver. 3.1)
Final angle assignmentType: PROJECTION MATCHING
FSC plot (resolution estimation)

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