Article Synopsis
- Individual free fatty acids (FAs) interact with various G protein-coupled receptors, influencing metabolic balance, notably through the identification of GPR120, linked to several metabolic diseases.
- Researchers used cryo-electron microscopy to examine six structures of GPR120 with FA hormones or synthetic ligands, revealing how specific residues in the receptor's pocket recognize different types of fatty acids.
- The study's findings on how GPR120 differentiates between double and single bonds could guide the development of targeted drugs for metabolic disorders.
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Article Abstract
Individual free fatty acids (FAs) play important roles in metabolic homeostasis, many through engagement with more than 40G protein-coupled receptors. Searching for receptors to sense beneficial omega-3 FAs of fish oil enabled the identification of GPR120, which is involved in a spectrum of metabolic diseases. Here, we report six cryo-electron microscopy structures of GPR120 in complex with FA hormones or TUG891 and G or G trimers. Aromatic residues inside the GPR120 ligand pocket were responsible for recognizing different double-bond positions of these FAs and connect ligand recognition to distinct effector coupling. We also investigated synthetic ligand selectivity and the structural basis of missense single-nucleotide polymorphisms. We reveal how GPR120 differentiates rigid double bonds and flexible single bonds. The knowledge gleaned here may facilitate rational drug design targeting to GPR120.
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