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TitleStructural basis for the ligand recognition and signaling of free fatty acid receptors.
Journal, issue, pagesSci Adv, Vol. 10, Issue 2, Page eadj2384, Year 2024
Publish dateJan 12, 2024
AuthorsXuan Zhang / Abdul-Akim Guseinov / Laura Jenkins / Kunpeng Li / Irina G Tikhonova / Graeme Milligan / Cheng Zhang /
PubMed AbstractFree 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.
External linksSci Adv / PubMed:38198545 / PubMed Central
MethodsEM (single particle)
Resolution3.06 - 3.6 Å
Structure data

EMDB-41007, PDB-8t3o:
Cryo-EM structure of the TUG-891 bound FFA4-Gq complex
Method: EM (single particle) / Resolution: 3.06 Å

EMDB-41008, PDB-8t3q:
Cryo-EM structure of the DHA bound FFA4-Gq complex
Method: EM (single particle) / Resolution: 3.14 Å

EMDB-41010, PDB-8t3s:
Cryo-EM structure of the Butyrate bound FFA2-Gq complex
Method: EM (single particle) / Resolution: 3.07 Å

EMDB-41013, PDB-8t3v:
Cryo-EM structure of the DHA bound FFA1-Gq complex
Method: EM (single particle) / Resolution: 3.39 Å

EMDB-41014: Cryo-EM structure of the DHA bound FFA1-Gq complex(mask on receptor)
Method: EM (single particle) / Resolution: 3.6 Å

Chemicals

ChemComp-YN9:
3-{4-[(4-fluoro-4'-methyl[1,1'-biphenyl]-2-yl)methoxy]phenyl}propanoic acid

ChemComp-2Y5:
(2R)-1-{[(R)-hydroxy{[(1R,2R,3R,4R,5S,6R)-2,3,5,6-tetrahydroxy-4-(phosphonooxy)cyclohexyl]oxy}phosphoryl]oxy}-3-(octadecanoyloxy)propan-2-yl (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate

ChemComp-PLM:
PALMITIC ACID / Palmitic acid

ChemComp-HXA:
DOCOSA-4,7,10,13,16,19-HEXAENOIC ACID / Docosahexaenoic acid

ChemComp-BUA:
butanoic acid / Butyric acid

ChemComp-CLR:
CHOLESTEROL / Cholesterol

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / GPCR / Complex / agonist

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