Single hormone or synthetic agonist induces Gs/Gicoupling selectivity of EP receptors via distinct binding modes and propagating paths

• DOI: 10.1073/pnas.2216329120
• Publication Date: 2023-07-21T17:44:31Z
• Authors: Shen-Ming Huang; Meng-Yao Xiong; Lei Liu; Jianqiang Mu; Ming-Wei Wang; Ying-Li Jia; Kui Cai; Lu Tie; Chao Zhang; Sheng Cao; Xin Wen; Jia-Le Wang; Sheng-Chao Guo; Yu Li; Chang-Xiu Qu; Qing-Tao He; Bo-Yang Cai; Chenyang Xue; Shiyi Gan; Yihe Xie; Xin Cong; Zhao Yang; Wei Kong; Shuo Li; Zijian Li; Peng Xiao; Fan Yang; Xiao Yu; You-Fei Guan; Xiaoyan Zhang; Zhongmin Liu; Bao-Xue Yang; Yang Du; Jin-Peng Sun
• Keywords: 0301 basic medicine; 03 medical and health sciences; Receptors, Prostaglandin; Receptors, Prostaglandin E, EP3 Subtype; GTP-Binding Protein alpha Subunits, Gs; Biological Sciences; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Dinoprostone; Hormones; Signal Transduction

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 STKE2001, re15 (2001); L. Hein, J. D. Altman, B.K. Kobilka,Nature402, 181–184 (1999); Y. Daaka, L. M. Luttrell, R. J. Lefkowitz,Nature390, 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 Gs-biased signaling, but not Giactivation downstream of EP4, showed beneficial effects for both KI and NDI treatments. Notably, by solving Cryo-electron microscope (cryo-EM) structures of EP3-Gi, EP4-Gs, and EP4-Giin complex with endogenous prostaglandin E2(PGE2)or two synthetic agonists and comparing with PGE2-EP2-Gsstructures, we found that unique primary sequences of prostaglandin E2 receptor (EP) receptors and distinct conformational states of the EP4 ligand pocket govern the Gs/Gitransducer coupling selectivity through different structural propagation paths, especially via TM6 and TM7, to generate selective cytoplasmic structural features. In particular, the orientation of the PGE2ω-chain and two distinct pockets encompassing agonist L902688 of EP4 were differentiated by their Gs/Gicoupling ability. Further, we identified common and distinct features of cytoplasmic side of EP receptors for Gs/Gicoupling and provide a structural basis for selective and biased agonist design of EP4 with therapeutic potential.