8gd9
Cryo-EM Structure of the Prostaglandin E2 Receptor 4 Coupled to G Protein
Structural highlights
DiseaseGNAS2_HUMAN Pseudopseudohypoparathyroidism;Pseudohypoparathyroidism type 1A;Progressive osseous heteroplasia;Polyostotic fibrous dysplasia;Monostotic fibrous dysplasia;Pseudohypoparathyroidism type 1C;Pseudohypoparathyroidism type 1B;McCune-Albright syndrome. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Most affected individuals have defects in methylation of the gene. In some cases microdeletions involving the STX16 appear to cause loss of methylation at exon A/B of GNAS, resulting in PHP1B. Paternal uniparental isodisomy have also been observed. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionGNAS2_HUMAN Guanine nucleotide-binding proteins (G proteins) function as transducers in numerous signaling pathways controlled by G protein-coupled receptors (GPCRs) (PubMed:17110384). Signaling involves the activation of adenylyl cyclases, resulting in increased levels of the signaling molecule cAMP (PubMed:26206488, PubMed:8702665). GNAS functions downstream of several GPCRs, including beta-adrenergic receptors (PubMed:21488135). Stimulates the Ras signaling pathway via RAPGEF2 (PubMed:12391161).[1] [2] [3] [4] [5] Publication Abstract from PubMedTo 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) omega-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. Single hormone or synthetic agonist induces G(s)/G(i) coupling selectivity of EP receptors via distinct binding modes and propagating paths.,Huang SM, Xiong MY, Liu L, Mu J, Wang MW, Jia YL, Cai K, Tie L, Zhang C, Cao S, Wen X, Wang JL, Guo SC, Li Y, Qu CX, He QT, Cai BY, Xue C, Gan S, Xie Y, Cong X, Yang Z, Kong W, Li S, Li Z, Xiao P, Yang F, Yu X, Guan YF, Zhang X, Liu Z, Yang BX, Du Y, Sun JP Proc Natl Acad Sci U S A. 2023 Jul 25;120(30):e2216329120. doi: , 10.1073/pnas.2216329120. Epub 2023 Jul 21. PMID:37478163[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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