+Open data
-Basic information
Entry | Database: PDB / ID: 8t3v | ||||||
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Title | Cryo-EM structure of the DHA bound FFA1-Gq complex | ||||||
Components |
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Keywords | MEMBRANE PROTEIN / GPCR / agonist | ||||||
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) Mus musculus (house mouse) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.39 Å | ||||||
Authors | Zhang, X. / Tikhonova, I. / Milligan, G. / Zhang, C. | ||||||
Funding support | United States, 1items
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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
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8t3v.cif.gz | 209.1 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8t3v.ent.gz | 162.8 KB | Display | PDB format |
PDBx/mmJSON format | 8t3v.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8t3v_validation.pdf.gz | 1.5 MB | Display | wwPDB validaton report |
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Full document | 8t3v_full_validation.pdf.gz | 1.5 MB | Display | |
Data in XML | 8t3v_validation.xml.gz | 42.8 KB | Display | |
Data in CIF | 8t3v_validation.cif.gz | 62.8 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/t3/8t3v ftp://data.pdbj.org/pub/pdb/validation_reports/t3/8t3v | HTTPS FTP |
-Related structure data
Related structure data | 41013MC 8t3oC 8t3qC 8t3sC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG
#1: Protein | Mass: 26569.172 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNAQ / Production host: Spodoptera frugiperda (fall armyworm) |
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#2: Protein | Mass: 37516.941 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873 |
#3: Protein | Mass: 6261.229 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768 |
-Antibody / Protein , 2 types, 2 molecules NR
#4: Antibody | Mass: 28634.797 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm) |
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#5: Protein | Mass: 29395.521 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: FFAR1, GPR40 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O14842 |
-Non-polymers , 2 types, 2 molecules
#6: Chemical | ChemComp-CLR / |
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#7: Chemical | ChemComp-HXA / |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: DHA-FFA1-miniGq complex / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT |
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Molecular weight | Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Spodoptera frugiperda (fall armyworm) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 800 nm |
Image recording | Electron dose: 61.6 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
-Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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3D reconstruction | Resolution: 3.39 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 305318 / Symmetry type: POINT |