Single hormone or synthetic agonist induces G s /G i coupling selectivity of EP receptors via distinct binding modes and propagating paths.

Autor: Huang SM; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China., Xiong MY; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China.; Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China., Liu L; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Mu J; Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China., Wang MW; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Jia YL; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China., Cai K; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China., Tie L; Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China., Zhang C; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Cao S; School of Medicine, Kobilka Institute of Innovative Drug Discovery, Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China., Wen X; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Wang JL; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China., Guo SC; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China., Li Y; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China., Qu CX; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China., He QT; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China., Cai BY; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China., Xue C; Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China., Gan S; School of Medicine, Kobilka Institute of Innovative Drug Discovery, Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China., Xie Y; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China., Cong X; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China., Yang Z; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Kong W; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China., Li S; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China., Li Z; Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Research, Beijing 100191, China.; Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing 100191, P. R. China., Xiao P; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Yang F; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China.; Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Yu X; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China., Guan YF; Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China., Zhang X; Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China., Liu Z; Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China., Yang BX; Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China., Du Y; School of Medicine, Kobilka Institute of Innovative Drug Discovery, Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China., Sun JP; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China.; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.; Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing 100191, P. R. China.; Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 Jul 25; Vol. 120 (30), pp. e2216329120. Date of Electronic Publication: 2023 Jul 21.
DOI: 10.1073/pnas.2216329120
Abstrakt: To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize the same hormone, and 2) different cellular effectors couple to the same hormone-receptor pair [R.P. Xiao, Sci STKE 2001 , re15 (2001); L. Hein, J. D. Altman, B.K. Kobilka, Nature 402 , 181-184 (1999); Y. Daaka, L. M. Luttrell, R. J. Lefkowitz, Nature 390 , 88-91 (1997)]. Not only these questions lie in the heart of hormone actions and receptor signaling but also dissecting mechanisms underlying these questions could offer therapeutic routes for refractory diseases, such as kidney injury (KI) or X-linked nephrogenic diabetes insipidus (NDI). Here, we identified that G s -biased signaling, but not G i activation downstream of EP4, showed beneficial effects for both KI and NDI treatments. Notably, by solving Cryo-electron microscope (cryo-EM) structures of EP3-G i , EP4-G s , and EP4-G i in complex with endogenous prostaglandin E 2 (PGE 2 )or two synthetic agonists and comparing with PGE 2 -EP2-G s structures, we found that unique primary sequences of prostaglandin E2 receptor (EP) receptors and distinct conformational states of the EP4 ligand pocket govern the G s /G i transducer coupling selectivity through different structural propagation paths, especially via TM6 and TM7, to generate selective cytoplasmic structural features. In particular, the orientation of the PGE 2 ω-chain and two distinct pockets encompassing agonist L902688 of EP4 were differentiated by their G s /G i coupling ability. Further, we identified common and distinct features of cytoplasmic side of EP receptors for G s /G i coupling and provide a structural basis for selective and biased agonist design of EP4 with therapeutic potential.
Databáze: MEDLINE
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