Journal: Science / Year: 2023 Title: Unsaturated bond recognition leads to biased signal in a fatty acid receptor. Authors: Chunyou Mao / Peng Xiao / Xiao-Na Tao / Jiao Qin / Qing-Tao He / Chao Zhang / Sheng-Chao Guo / Ya-Qin Du / Li-Nan Chen / Dan-Dan Shen / Zhi-Shuai Yang / Han-Qiong Zhang / Shen-Ming Huang / ...Authors: Chunyou Mao / Peng Xiao / Xiao-Na Tao / Jiao Qin / Qing-Tao He / Chao Zhang / Sheng-Chao Guo / Ya-Qin Du / Li-Nan Chen / Dan-Dan Shen / Zhi-Shuai Yang / Han-Qiong Zhang / Shen-Ming Huang / Yong-Hao He / Jie Cheng / Ya-Ni Zhong / Pan Shang / Jun Chen / Dao-Lai Zhang / Qian-Lang Wang / Mei-Xia Liu / Guo-Yu Li / Yongyuan Guo / H Eric Xu / Chuanxin Wang / Cheng Zhang / Shiqing Feng / Xiao Yu / Yan Zhang / Jin-Peng Sun / 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 ...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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