G protein-coupled receptors (GPCRs) have evolved to recognize incredibly diverse extracellular ligands while sharing a common architecture and structurally conserved intracellular signaling partners. It remains unclear how binding of diverse ligands brings about GPCR activation, the common structural change that enables intracellular signaling. Here, we identify highly conserved networks of water-mediated interactions that play a central role in activation. Using atomic-level simulations of diverse GPCRs, we show that most of the water molecules in GPCR crystal structures are highly mobile. Several water molecules near the G protein-coupling interface, however, are stable. These water molecules form two kinds of polar networks that are conserved across diverse GPCRs: () a network that is maintained across the inactive and the active states and () a network that rearranges upon activation. Comparative analysis of GPCR crystal structures independently confirms the striking conservation of water-mediated interaction networks. These conserved water-mediated interactions near the G protein-coupling region, along with diverse water-mediated interactions with extracellular ligands, have direct implications for structure-based drug design and GPCR engineering.
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http://dx.doi.org/10.1073/pnas.1809251116 | DOI Listing |
Nat Commun
January 2025
Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Int J Mol Sci
December 2024
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
G protein-coupled receptors (GPCRs) play essential roles in numerous physiological processes and are key targets for drug development. Among them, adhesion GPCRs (aGPCRs) stand out for their unique domain structures and diverse functions. ADGRG2 is a member of the aGPCR family and is involved in the regulation of various systems in the human body, including reproductive, nervous, cardiovascular, and endocrine systems.
View Article and Find Full Text PDFInsects
November 2024
Shandong Engineering Research Center for Environment-Friendly Agricultural Pest Management, College of Plant Health and Medicine, Qingdao Agricultural University, Qingdao 266109, China.
Neuropeptide (abbreviated as ) is a recently discovered peptide that is present in many arthropods and is the ligand of the , a member of the G protein-coupled receptors (GPCRs) superfamily, which plays a regulatory role in diverse physiological processes such as feeding, circadian rhythm, insulin production, lipid metabolism, growth, and reproduction. However, the function of this gene in aphids is still unknown. Here, we characterized and determined the potential role of / signaling in the pea aphid, , which is a notorious pest in agriculture.
View Article and Find Full Text PDFInt J Mol Sci
December 2024
Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Republic of Korea.
Odorant receptors (ORs), which constitute approximately 50% of all human G protein-coupled receptors, are increasingly recognized for their diverse roles beyond odor perception, including functions in various pathological conditions like brain diseases and cancers. However, the roles of ORs in glioblastoma (GBM), the most aggressive primary brain tumor with a median survival of only 15 months, remain largely unexplored. Here, we performed an integrated transcriptomic analysis combining The Cancer Genome Atlas RNA-seq and single-cell RNA sequencing data from GBM patients to uncover cell-type-specific roles of ORs within the tumor and its microenvironment.
View Article and Find Full Text PDFPharmacol Res
January 2025
Department of Cardiology, Changzheng Hospital, The Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China. Electronic address:
G protein-coupled receptors (GPCRs) represent the largest family of membrane receptors and are highly effective targets for therapeutic drugs. GPCRs couple different downstream effectors, including G proteins (such as Gi/o, Gs, G12, and Gq) and β-arrestins (such as β-arrestin 1 and β-arrestin 2) to mediate diverse cellular and physiological responses. Biased signaling allows for the specific activation of certain pathways from the full range of receptors' signaling capabilities.
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