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Open data
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Basic information
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Title | Cryo-EM structure of the DHA bound FFA4-Gq complex | |||||||||
![]() | DHA-FFA4-miniGq | |||||||||
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![]() | GPCR / agonist / MEMBRANE PROTEIN | |||||||||
Function / homology | ![]() negative regulation of somatostatin secretion / ghrelin secretion / positive regulation of glucagon secretion / Free fatty acid receptors / regulation of glucose transmembrane transport / taste receptor activity / hormone secretion / arrestin family protein binding / white fat cell differentiation / negative regulation of cytokine production ...negative regulation of somatostatin secretion / ghrelin secretion / positive regulation of glucagon secretion / Free fatty acid receptors / regulation of glucose transmembrane transport / taste receptor activity / hormone secretion / arrestin family protein binding / white fat cell differentiation / negative regulation of cytokine production / ciliary membrane / negative regulation of interleukin-1 beta production / endocytic vesicle / positive regulation of osteoblast differentiation / brown fat cell differentiation / cellular response to hormone stimulus / positive regulation of brown fat cell differentiation / peptide binding / fatty acid binding / G protein-coupled receptor activity / negative regulation of inflammatory response / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / cilium / 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 / retina development in camera-type eye / Ca2+ pathway / positive regulation of cold-induced thermogenesis / 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 / Ras protein signal transduction / G alpha (q) signalling events / Extra-nuclear estrogen signaling / cell population proliferation / positive regulation of ERK1 and ERK2 cascade / endosome membrane / inflammatory response / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / negative regulation of apoptotic process / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytoplasm / cytosol Similarity search - Function | |||||||||
Biological species | ![]() ![]() ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.14 Å | |||||||||
![]() | Zhang X / Tikhonova I / Milligan G / Zhang C | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Structural basis for the ligand recognition and signaling of free fatty acid receptors. Authors: Xuan Zhang / Abdul-Akim Guseinov / Laura Jenkins / Kunpeng Li / Irina G Tikhonova / Graeme Milligan / Cheng Zhang / ![]() ![]() Abstract: Free fatty acid receptors 1 to 4 (FFA1 to FFA4) are class A G protein-coupled receptors (GPCRs). FFA1 to FFA3 share substantial sequence similarity, whereas FFA4 is unrelated. However, FFA1 and FFA4 ...Free fatty acid receptors 1 to 4 (FFA1 to FFA4) are class A G protein-coupled receptors (GPCRs). FFA1 to FFA3 share substantial sequence similarity, whereas FFA4 is unrelated. However, FFA1 and FFA4 are activated by long-chain fatty acids, while FFA2 and FFA3 respond to short-chain fatty acids generated by intestinal microbiota. FFA1, FFA2, and FFA4 are potential drug targets for metabolic and inflammatory conditions. Here, we determined the active structures of FFA1 and FFA4 bound to docosahexaenoic acid, FFA4 bound to the synthetic agonist TUG-891, and butyrate-bound FFA2, each complexed with an engineered heterotrimeric G protein (miniG), by cryo-electron microscopy. Together with computational simulations and mutagenesis studies, we elucidated the similarities and differences in the binding modes of fatty acid ligands to their respective GPCRs. Our findings unveiled distinct mechanisms of receptor activation and G protein coupling. We anticipate that these outcomes will facilitate structure-based drug development and underpin future research on this group of GPCRs. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 59.7 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 18.7 KB 18.7 KB | Display Display | ![]() |
Images | ![]() | 32.2 KB | ||
Filedesc metadata | ![]() | 6.3 KB | ||
Others | ![]() ![]() | 59.4 MB 59.4 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8t3qMC ![]() 8t3oC ![]() 8t3sC ![]() 8t3vC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | DHA-FFA4-miniGq | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.828 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: DHA-FFA4-miniGq-half B
File | emd_41008_half_map_1.map | ||||||||||||
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Annotation | DHA-FFA4-miniGq-half_B | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: DHA-FFA4-miniGq-half A
File | emd_41008_half_map_2.map | ||||||||||||
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Annotation | DHA-FFA4-miniGq-half_A | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
-Entire : DHA-FFA4-miniGq complex
Entire | Name: DHA-FFA4-miniGq complex |
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Components |
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-Supramolecule #1: DHA-FFA4-miniGq complex
Supramolecule | Name: DHA-FFA4-miniGq complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5 |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Guanine nucleotide-binding protein G(q)
Macromolecule | Name: Guanine nucleotide-binding protein G(q) / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 26.670275 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: VSAEDKAAAE RSKMIDKNLR EDGEKARRTL RLLLLGADNS GKSTIVKQMT SGIFETKFQV DKVNFHMFDV GGQRDERRKW IQCFNDVTA IIFVVDSSDY NRLQEALNDF KSIWNNRWLR TISVILFLNK QDLLAEKVLA GKSKIEDYFP EFARYTTPED A TPEPGEDP ...String: VSAEDKAAAE RSKMIDKNLR EDGEKARRTL RLLLLGADNS GKSTIVKQMT SGIFETKFQV DKVNFHMFDV GGQRDERRKW IQCFNDVTA IIFVVDSSDY NRLQEALNDF KSIWNNRWLR TISVILFLNK QDLLAEKVLA GKSKIEDYFP EFARYTTPED A TPEPGEDP RVTRAKYFIR KEFVDISTAS GDGRHICYPH FTCAVDTENA RRIFNDCKDI ILQMNLREYN LV |
-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: ![]() |
Molecular weight | Theoretical: 37.516941 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLII WDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR FLDDNQIVTS S GDTTCALW ...String: SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLII WDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR FLDDNQIVTS S GDTTCALW DIETGQQTTT FTGHTGDVMS LSLAPDTRLF VSGACDASAK LWDVREGMCR QTFTGHESDI NAICFFPNGN AF ATGSDDA TCRLFDLRAD QELMTYSHDN IICGITSVSF SKSGRLLLAG YDDFNCNVWD ALKADRAGVL AGHDNRVSCL GVT DDGMAV ATGSWDSFLK IWNGSS UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-Macromolecule #3: scFv16
Macromolecule | Name: scFv16 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 28.634797 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS AGGGGSGGGG SGGGGSADIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS AGGGGSGGGG SGGGGSADIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL LEENLYFQGA SHHHHHHHH |
-Macromolecule #4: 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: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 6.261229 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: TASIAQARKL VEQLKMEANI DRIKVSKAAA DLMAYCEAHA KEDPLLTPVP ASENPFR UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-Macromolecule #5: Free fatty acid receptor 4
Macromolecule | Name: Free fatty acid receptor 4 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 34.67048 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: RTRFPFFSDV KGDHRLVLAA VETTVLVLIF AVSLLGNVCA LVLVARRRRR GATACLVLNL FCADLLFISA IPLVLAVRWT EAWLLGPVA CHLLFYVMTL SGSVTILTLA AVSLERMVCI VHLQRGVRGP GRRARAVLLA LIWGYSAVAA LPLCVFFRVV P QRLPGADQ ...String: RTRFPFFSDV KGDHRLVLAA VETTVLVLIF AVSLLGNVCA LVLVARRRRR GATACLVLNL FCADLLFISA IPLVLAVRWT EAWLLGPVA CHLLFYVMTL SGSVTILTLA AVSLERMVCI VHLQRGVRGP GRRARAVLLA LIWGYSAVAA LPLCVFFRVV P QRLPGADQ EISICTLIWP TIPGEISWDV SFVTLNFLVP GLVIVISYSK ILQITKASRK RLTVSLAYSE SHQIRVSQQD FR LFRTLFL LMVSFFIMWS PIIITILLIL IQNFKQDLVI WPSLFFWVVA FTFANSALNP ILYNMTLCRN E UniProtKB: Free fatty acid receptor 4 |
-Macromolecule #6: DOCOSA-4,7,10,13,16,19-HEXAENOIC ACID
Macromolecule | Name: DOCOSA-4,7,10,13,16,19-HEXAENOIC ACID / type: ligand / ID: 6 / Number of copies: 1 / Formula: HXA |
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Molecular weight | Theoretical: 328.488 Da |
Chemical component information | ![]() ChemComp-HXA: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
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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: 55.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.0 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Startup model | Type of model: NONE |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.14 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 380284 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |