+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-41010 | |||||||||
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Title | Cryo-EM structure of the Butyrate bound FFA2-Gq complex | |||||||||
Map data | Butyrate-FFA2-miniGq | |||||||||
Sample |
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Keywords | GPCR / agonist / MEMBRANE PROTEIN | |||||||||
Function / homology | Function and homology information 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 ...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 / 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 / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Mus musculus (house mouse) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.07 Å | |||||||||
Authors | Zhang X / Tikhonova I / Milligan G / Zhang C | |||||||||
Funding support | United States, 1 items
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Citation | Journal: Sci Adv / Year: 2024 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 | emd_41010.map.gz | 59.8 MB | EMDB map data format | |
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Header (meta data) | emd-41010-v30.xml emd-41010.xml | 19.2 KB 19.2 KB | Display Display | EMDB header |
Images | emd_41010.png | 28.4 KB | ||
Filedesc metadata | emd-41010.cif.gz | 6.4 KB | ||
Others | emd_41010_half_map_1.map.gz emd_41010_half_map_2.map.gz | 59.4 MB 59.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-41010 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-41010 | HTTPS FTP |
-Related structure data
Related structure data | 8t3sMC 8t3oC 8t3qC 8t3vC 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_41010.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Annotation | Butyrate-FFA2-miniGq | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.826 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: Butyrate-FFA2-miniGq-half A
File | emd_41010_half_map_1.map | ||||||||||||
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Annotation | Butyrate-FFA2-miniGq-half_A | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Butyrate-FFA2-miniGq-half B
File | emd_41010_half_map_2.map | ||||||||||||
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Annotation | Butyrate-FFA2-miniGq-half_B | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Butyrate-FFA2-miniGq complex
Entire | Name: Butyrate-FFA2-miniGq complex |
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Components |
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-Supramolecule #1: Butyrate-FFA2-miniGq complex
Supramolecule | Name: Butyrate-FFA2-miniGq complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Guanine nucleotide-binding protein G(q) subunit alpha
Macromolecule | Name: 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: 26.670275 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
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: Homo sapiens (human) |
Molecular weight | Theoretical: 37.516941 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
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: 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: 6.261229 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: TASIAQARKL VEQLKMEANI DRIKVSKAAA DLMAYCEAHA KEDPLLTPVP ASENPFR UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-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: Mus musculus (house mouse) |
Molecular weight | Theoretical: 25.331432 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS AADIVMTQAT SSVPVTPGES VSISCRSSKS LLHSNGNTYL Y WFLQRPGQ ...String: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS AADIVMTQAT SSVPVTPGES VSISCRSSKS LLHSNGNTYL Y WFLQRPGQ SPQLLIYRMS NLASGVPDRF SGSGSGTAFT LTISRLEAED VGVYYCMQHL EYPLTFGAGT KLEL |
-Macromolecule #5: Free fatty acid receptor 2
Macromolecule | Name: Free fatty acid receptor 2 / 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: 29.192848 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: PDWKSSLILM AYIIIFLTGL PANLLALRAF VGRIRQPQPA PVHILLLSLT LADLLLLLLL PFKIIEAASN LPKVVCALTS FGFYSSIYC STWLLAGISI ERYLGVAFPV QYKLSRRPLY GVIAALVAWV MSFGHCTIVI IVQYLCYENF TDNQLDVVLP V RLELCLVL ...String: PDWKSSLILM AYIIIFLTGL PANLLALRAF VGRIRQPQPA PVHILLLSLT LADLLLLLLL PFKIIEAASN LPKVVCALTS FGFYSSIYC STWLLAGISI ERYLGVAFPV QYKLSRRPLY GVIAALVAWV MSFGHCTIVI IVQYLCYENF TDNQLDVVLP V RLELCLVL FFIPMAVTIF CYWRFVWIML SQPGAQRRRR AVGLAVVTLL NFLVCFGPYN VSHLVGYHQR KSPWWRSIAV VF SSLNASL DPLLFYFSSS V |
-Macromolecule #6: butanoic acid
Macromolecule | Name: butanoic acid / type: ligand / ID: 6 / Number of copies: 1 / Formula: BUA |
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Molecular weight | Theoretical: 88.105 Da |
Chemical component information | ChemComp-BUA: |
-Macromolecule #7: CHOLESTEROL
Macromolecule | Name: CHOLESTEROL / type: ligand / ID: 7 / Number of copies: 1 / Formula: CLR |
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Molecular weight | Theoretical: 386.654 Da |
Chemical component information | ChemComp-CLR: |
-Macromolecule #8: PALMITIC ACID
Macromolecule | Name: PALMITIC ACID / type: ligand / ID: 8 / Number of copies: 2 / Formula: PLM |
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Molecular weight | Theoretical: 256.424 Da |
Chemical component information | ChemComp-PLM: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm |
Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 61.6 e/Å2 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: NONE |
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Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.07 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 393952 |