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- EMDB-28164: Structure of FFAR1-Gq complex bound to DHA -

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Entry
Database: EMDB / ID: EMD-28164
TitleStructure of FFAR1-Gq complex bound to DHA
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: DOCOSA-4,7,10,13,16,19-HEXAENOIC 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 / ion channel modulating, G protein-coupled receptor signaling pathway / 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 ...bioactive lipid receptor activity / Free fatty acid receptors / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / ion channel modulating, G protein-coupled receptor signaling pathway / 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 / viral release from host cell by cytolysis / peptidoglycan catabolic process / G protein-coupled receptor activity / 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 activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / ADP signalling through P2Y purinoceptor 12 / positive regulation of insulin secretion / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / sensory perception of taste / GPER1 signaling / G-protein beta-subunit binding / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / G alpha (12/13) signalling events / signaling receptor complex adaptor activity / cell wall macromolecule catabolic process / Thrombin signalling through proteinase activated receptors (PARs) / glucose homeostasis / retina development in camera-type eye / GTPase binding / lysozyme / Ca2+ pathway / lysozyme activity / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / host cell cytoplasm / Extra-nuclear estrogen signaling / defense response to bacterium / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / lipid binding / synapse / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
GPR40 receptor fatty acid / G protein-coupled receptor 40-related receptor / Endolysin T4 type / T4-type lysozyme / Glycoside hydrolase, family 24 / Lysozyme domain superfamily / Phage lysozyme / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain ...GPR40 receptor fatty acid / G protein-coupled receptor 40-related receptor / Endolysin T4 type / T4-type lysozyme / Glycoside hydrolase, family 24 / Lysozyme domain superfamily / Phage lysozyme / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / 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) / Lysozyme-like domain superfamily / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Free fatty acid receptor 1 / Endolysin / 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: 2.8 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 15, 2022-
Header (metadata) releaseMay 24, 2023-
Map releaseMay 24, 2023-
UpdateMay 31, 2023-
Current statusMay 31, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28164.png

Downloads & links

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Map

FileDownload / File: emd_28164.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.08 Å
Density
Contour LevelBy AUTHOR: 0.0122
Minimum - Maximum-0.054433282 - 0.11740935
Average (Standard dev.)0.00005235229 (±0.0028085485)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 216.00002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_28164_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_28164_half_map_2.map
Projections & Slices
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Histogram (log scale)

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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: DOCOSA-4,7,10,13,16,19-HEXAENOIC 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

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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

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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 / EC number: lysozyme
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

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Macromolecule #6: DOCOSA-4,7,10,13,16,19-HEXAENOIC ACID

MacromoleculeName: DOCOSA-4,7,10,13,16,19-HEXAENOIC ACID / type: ligand / ID: 6 / Number of copies: 1 / Formula: HXA
Molecular weightTheoretical: 328.488 Da
Chemical component information

ChemComp-HXA:
DOCOSA-4,7,10,13,16,19-HEXAENOIC ACID / Docosahexaenoic 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 chloridesodium 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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.4000000000000001 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 1.4 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 7795974
Startup modelType of model: NONE
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION (ver. 3.1)
Final angle assignmentType: PROJECTION MATCHING
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 480447
FSC plot (resolution estimation)

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