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Mao, Chunyou; Xiao, Peng; Tao, Xiao-Na; Qin, Jiao; He, Qing-Tao; Zhang, Chao; Guo, Sheng-Chao; Du, Ya-Qin; Chen, Li-Nan; Shen, Dan-Dan; Yang, Zhi-Shuai; Zhang, Han-Qiong; Huang, Shen-Ming; He, Yong-Hao; Cheng, Jie; Zhong, Ya-Ni; Shang, Pan; Chen, Jun; Zhang, Dao-Lai; Wang, Qian-Lang; Liu, Mei-Xia; Li, Guo-Yu; Guo, Yongyuan; Xu, H Eric; Wang, Chuanxin; Zhang, Cheng; Feng, Shiqing; Yu, Xiao; Zhang, Yan; Sun, Jin-Peng
Science (American Association for the Advancement of Science), 04/2023, Volume: 380, Issue: 6640Journal Article
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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