Dataset Information

Regulating G protein-coupled receptors by topological inversion.

ABSTRACT: G protein-coupled receptors (GPCRs) are a family of proteins containing seven transmembrane helices, with the N- and C-terminus of the protein located at the extracellular space and cytosol, respectively. Here, we report that ceramide or related sphingolipids might invert the topology of many GPCRs that contain a GXXXN motif in their first transmembrane helix. The functional significance of this topological regulation is illustrated by the CCR5 chemokine receptor. In the absence of lipopolysaccharide (LPS), CCR5 adopts a topology consistent with that of GPCR, allowing mouse peritoneal macrophages to migrate toward its ligand CCL5. LPS stimulation results in increased production of dihydroceramide, which inverts the topology of CCR5, preventing macrophages from migrating toward CCL5. These results suggest that GPCRs may not always adopt the same topology and can be regulated through topological inversion. Editorial note:This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that major issues remain unresolved (see decision letter).

SUBMITTER: Denard B

PROVIDER: S-EPMC6400500 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Regulating G protein-coupled receptors by topological inversion.

Denard Bray B Han Sungwon S Kim JungYeon J Ross Elliott M EM Ye Jin J

eLife 20190305

G protein-coupled receptors (GPCRs) are a family of proteins containing seven transmembrane helices, with the N- and C-terminus of the protein located at the extracellular space and cytosol, respectively. Here, we report that ceramide or related sphingolipids might invert the topology of many GPCRs that contain a GXXXN motif in their first transmembrane helix. The functional significance of this topological regulation is illustrated by the CCR5 chemokine receptor. In the absence of lipopolysacch ...[more]

PMID: 30835201

Similar Datasets

Project description:Introduction: Ischemic stroke (IS) is a detrimental neurological disease with limited treatment options. Recanalization of blocked blood vessels and restoring blood supply to ischemic brain tissue are crucial for post-stroke rehabilitation. The decoction Naodesheng (NDS) composed of five Chinese botanical drugs, including Panax notoginseng (Burk.) F. H. Chen, Ligusticum chuanxiong Hort., Carthamus tinctorius L., Pueraria lobata (Willd.) Ohwi, and Crataegus pinnatifida Bge., is a blood-activating and stasis-removing herbal medicine commonly used for the clinical treatment of cerebrovascular diseases in China. However, the material basis of NDS on the effects of blood circulation improvement and vascular tone regulation remains unclear. Methods: A database comprising 777 chemical metabolites of NDS was constructed. Then, the interactions between various herbal metabolites of NDS and five vascular tone modulation G-protein-coupled receptors (GPCRs), including 5-HT1AR, 5-HT1BR, β2-AR, AT1R, and ETBR, were assessed by molecular docking. Using network analysis and vasomotor experiment of the cerebral basilar artery, the potential material basis underlying the vascular regulatory effects of NDS was further explored. Results: The Naodesheng Effective Component Group (NECG) was found to induce relaxation of rat basilar artery rings precontracted using Endothelin-1 (ET-1) and KCl in vitro in a dose-dependent manner. Several metabolites of NDS, including C. tinctorius, C. pinnatifida, and P. notoginseng, were found to be the main plant resources of metabolites with high docking scores. Furthermore, several metabolites in NDS, including formononetin-7-glucoside, hydroxybenzoyl-coumaric anhydride, methoxymecambridine, puerarol, and pyrethrin II, were found to target multiple vascular GPCRs. Metabolites with moderate-to-high binding energy were verified to have good rat basilar artery-relaxing effects, and the maximum artery relaxation effects of all three metabolites, namely, isorhamnetin, kaempferol, and daidzein, were found to exceed 90%. Moreover, metabolites of NDS were found to exert a synergistic effect by interacting with vascular GPCR targets, and these metabolites may contribute to the cerebrovascular regulatory function of NDS. Discussion: The study reports that various metabolites of NDS contribute to its vascular tone regulating effects and demonstrates the multi-component and multi-target characteristics of NDS. Among them, metabolites with moderate-to-high binding scores in NDS may play an important role in regulating vascular function.

Project description:The years 2000 and 2007 witnessed milestones in current understanding of G protein-coupled receptor (GPCR) structural biology. In 2000 the first GPCR, bovine rhodopsin, was crystallized and the structure was solved, while in 2007 the structure of β(2)-adrenergic receptor, the first GPCR with diffusible ligands, was determined owing to advances in microcrystallization and an insertion of the fast-folding lysozyme into the receptor. In parallel with those crystallographic studies, the biological and biochemical characterization of GPCRs has advanced considerably because those receptors are molecular targets for many of currently used drugs. Therefore, the mechanisms of activation and signal transduction to the cell interior deduced from known GPCRs structures are of the highest importance for drug discovery. These proteins are the most diversified membrane receptors encoded by hundreds of genes in our genome. They participate in processes responsible for vision, smell, taste and neuronal transmission in response to photons or binding of ions, hormones, peptides, chemokines and other factors. Although the GPCRs share a common seven-transmembrane α-helical bundle structure their binding sites can accommodate thousands of different ligands. The ligands, including agonists, antagonists or inverse agonists change the structure of the receptor. With bound agonists they can form a complex with a suitable G protein, be phosphorylated by kinases or bind arrestin. The discovered signaling cascades invoked by arrestin independently of G proteins makes the GPCR activating scheme more complex such that a ligand acting as an antagonist for G protein signaling can also act as an agonist in arrestin-dependent signaling. Additionally, the existence of multiple ligand-dependent partial activation states as well as dimerization of GPCRs result in a 'microprocessor-like' action of these receptors rather than an 'on-off' switch as was commonly believed only a decade ago.

Dataset Information

Regulating G protein-coupled receptors by topological inversion.

Publications

Regulating G protein-coupled receptors by topological inversion.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets