Structural basis for ligand recognition and activation of the prostanoid receptors
Xiu Li,
Xuan Zhang,
Xin Wen,
Daolai Zhang,
Changxiu Qu,
Xinyi Miao,
Wenkai Zhang,
Ru Zhang,
Guibing Liu,
Peng Xiao,
Jin-Peng Sun,
Weimin Gong
Affiliations
Xiu Li
Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026, China
Xuan Zhang
Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026, China; Corresponding author
Xin Wen
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, Jinan, Shandong 250012, China
Daolai Zhang
School of Pharmacy, Binzhou Medical University, Yantai, Shandong 264003, China
Changxiu Qu
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, Jinan, Shandong 250012, China
Xinyi Miao
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, Jinan, Shandong 250012, China
Wenkai Zhang
School of Pharmacy, Binzhou Medical University, Yantai, Shandong 264003, China
Ru Zhang
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, Jinan, Shandong 250012, China
Guibing Liu
Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026, China
Peng Xiao
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, Jinan, Shandong 250012, China; Corresponding author
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, Jinan, Shandong 250012, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing 100191, China; Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Corresponding author
Weimin Gong
Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026, China; Corresponding author
Summary: Prostaglandin F2α (PGF2α) and thromboxane A2 (TXA2) are endogenous arachidonic acid metabolites, modulating diverse physiological processes including inflammation and cardiovascular homeostasis through activating PGF2α receptor (FP) and TXA2 receptor (TP). Ligands targeting FP and TP have demonstrated efficacy in treating conditions like glaucoma and cardiovascular diseases in humans, as well as reproductive-related diseases in animals. Here, we present five cryoelectron microscopy structures illustrating FP and TP in complex with Gq and bound to PGF2α (endogenous ligand), latanoprost acid (a clinical drug), and two other synthetic agonists. Combined with mutational and functional studies, these structures reveal not only structural features for the specific recognition of endogenous ligands and attainment of receptor selectivity of FP and TP but also the common mechanisms of receptor activation and Gq protein coupling. The findings may enrich our knowledge of ligand recognition and signal transduction of the prostanoid receptor family and facilitate rational ligand design toward these two receptors.
