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Yorodumi- EMDB-28185: Structure of FFAR1-Gq complex bound to TAK-875 in a lipid nanodisc -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-28185 | |||||||||
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Title | Structure of FFAR1-Gq complex bound to TAK-875 in a lipid nanodisc | |||||||||
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Sample |
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Keywords | FFAR1 / 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 / 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 / positive regulation of insulin secretion / 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 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / 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 / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / glucose homeostasis / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ 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 / cell population proliferation / Ras protein signal transduction / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / lipid binding / synapse / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytoplasm / cytosol Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.4 Å | |||||||||
Authors | Kumari P / Inoue A / Chapman K / Lian P / Rosenbaum DM | |||||||||
Funding support | United States, 1 items
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Citation | Journal: 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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_28185.map.gz | 33.2 MB | EMDB map data format | |
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Header (meta data) | emd-28185-v30.xml emd-28185.xml | 20.5 KB 20.5 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_28185_fsc.xml | 7.5 KB | Display | FSC data file |
Images | emd_28185.png | 39.3 KB | ||
Others | emd_28185_half_map_1.map.gz emd_28185_half_map_2.map.gz | 27.2 MB 27.2 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-28185 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-28185 | HTTPS FTP |
-Validation report
Summary document | emd_28185_validation.pdf.gz | 859.5 KB | Display | EMDB validaton report |
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Full document | emd_28185_full_validation.pdf.gz | 859 KB | Display | |
Data in XML | emd_28185_validation.xml.gz | 13.1 KB | Display | |
Data in CIF | emd_28185_validation.cif.gz | 18.1 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-28185 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-28185 | HTTPS FTP |
-Related structure data
Related structure data | 8ejkMC 8eitC 8ejcC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_28185.map.gz / Format: CCP4 / Size: 35.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.07 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_28185_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_28185_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Free Fatty Acid Receptor1- G-Protein complex
Entire | Name: Free Fatty Acid Receptor1- G-Protein complex |
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Components |
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-Supramolecule #1: Free Fatty Acid Receptor1- G-Protein complex
Supramolecule | Name: Free Fatty Acid Receptor1- G-Protein complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: A modified Guanine nucleotide-binding protein G(q) subunit alpha
Macromolecule | Name: A modified Guanine nucleotide-binding protein G(q) subunit alpha type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 27.638461 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: 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 |
-Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Macromolecule | Name: 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 |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 37.41693 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: 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 |
-Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Macromolecule | Name: 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 |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 9.137474 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MGHHHHHHHH GGASNNTASI AQARKLVEQL KMEANIDRIK VSKAAADLMA YCEAHAKEDP LLTPVPASEN PFREKKFFCA IL |
-Macromolecule #4: scFv16
Macromolecule | Name: scFv16 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 34.930852 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: 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 |
-Macromolecule #5: Free fatty acid receptor 1
Macromolecule | Name: Free fatty acid receptor 1 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 54.298785 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: 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 |
-Macromolecule #6: [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3...
Macromolecule | Name: [(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 |
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Molecular weight | Theoretical: 524.625 Da |
Chemical component information | ChemComp-2YB: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 5 mg/mL | ||||||||||||||||||
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Buffer | pH: 7.5 Component:
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Vitrification | Cryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 1.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination 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 |