Unsaturated bond recognition leads to biased signal in a fatty acid receptor

On March 2, 2023, Jin-Peng Sun, Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, China, and his team published a paper titled “Unsaturated bond recognition leads to biased signal in a fatty acid receptor” in Science. They revealed how GPR120 differentiates rigid double bonds and flexible single bonds and may facilitate rational drug design targeting to GPR120.

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Individual free fatty acids (FAs) play important roles in metabolic homeostasis, many via engagement with more than 40 GPCRs. Searching for receptors to sense beneficial ω-3 FAs of fish oil enabled the identification of GPR120, involving with a spectrum of metabolic diseases. Here, we report six cryo-EM structures of GPR120 in complex with FA hormones or TUG891 and Gi or Giq 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 and may facilitate rational drug design targeting to GPR120.