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High Precision FRET at Single-molecule Level for Biomolecule Structure Determination
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Structural insights into endogenous ligand selectivity and activation mechanisms of FFAR1 and FFAR2

Yudun Ke1, Yimiao Huang1, Cuiying Yi2

  • 1School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China.

Cell Reports
|December 1, 2024
PubMed

Insights

Structural insights into free fatty acid receptors (FFARs) reveal how docosahexaenoic acid and butyrate bind, aiding drug discovery for metabolic and inflammatory diseases.

Area of Science:

  • Biochemistry and structural biology
  • G protein-coupled receptor (GPCR) research
  • Metabolic disease mechanisms

Background:

  • Free fatty acid receptors (FFARs) are crucial in metabolic regulation and are targets for treating metabolic and inflammatory diseases.
  • Understanding FFAR activation and ligand selectivity is vital for developing new therapeutics.

Purpose of the Study:

  • To elucidate the structural basis of endogenous ligand binding and activation in FFAR1 and FFAR2.
  • To provide insights for the rational design of FFAR-targeting drugs.

Main Methods:

  • Cryoelectron microscopy (cryo-EM) to determine high-resolution structures of FFAR1-DHA-Gi1 and FFAR2-butyrate-Gi1 complexes.
  • Computational analysis to identify potential allosteric binding sites.

Main Results:

  • Determined cryo-EM structures of human FFAR1 with docosahexaenoic acid (DHA) and FFAR2 with butyrate, complexed with Gi1 protein.
  • Identified distinct orthosteric ligand-binding pocket characteristics dictating receptor selectivity.
  • Revealed upward movement of helix V as the key activation mechanism upon ligand binding.
  • Discovered a potential allosteric ligand-binding pocket in FFAR2 through computational analysis.

Conclusions:

  • Structural data reveals key determinants of FFAR subfamily ligand selectivity.
  • The identified activation mechanism and binding pockets offer new avenues for drug development targeting FFARs.
  • These findings significantly advance the understanding of FFAR function in metabolic regulation.
Keywords:
CP: Molecular biologyFFAR1FFAR2GPCRStructural biologycryo-EMfree fatty acid receptorssignaling complex

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