ABSTRACT
Sphingosine-1-phosphate (S1P) is an important bioactive lipid molecule in cell membrane metabolism and binds to G protein-coupled S1P receptors (S1PRs) to regulate embryonic development, physiological homeostasis, and pathogenic processes in various organs. S1PRs are lipid-sensing receptors and are therapeutic targets for drug development, including potential treatment of COVID-19. Herein, we present five cryo-electron microscopy structures of S1PRs bound to diverse drug agonists and the heterotrimeric Gi protein. Our structural and functional assays demonstrate the different binding modes of chemically distinct agonists of S1PRs, reveal the mechanical switch that activates these receptors, and provide a framework for understanding ligand selectivity and G protein coupling.
Subject(s)
Sphingosine-1-Phosphate Receptors/agonists , Azetidines/chemistry , Azetidines/metabolism , Benzyl Compounds/chemistry , Benzyl Compounds/metabolism , Cryoelectron Microscopy , Humans , Molecular Dynamics Simulation , Protein Binding , Protein Structure, Quaternary , Signal Transduction , Sphingosine-1-Phosphate Receptors/genetics , Sphingosine-1-Phosphate Receptors/metabolismABSTRACT
Early diagnosis, early isolation, and early treatment are efficient solutions to control the COVID-19 pandemic. To achieve the accurate early diagnosis of SARS-CoV-2, a multiplex detection strategy is required for the cross-validation to solve the problem of "false negative" of the existing gold standard assay. Here, we present a multicomponent nucleic acid assay platform for SARS-CoV-2 detection based on lanthanide nanoparticle (LnNP)-tagging strategy. For targeting SARS-CoV-2's RNA fragments ORF1ab gene, RdRp gene, and E gene, three LnNP probes can be used simultaneously to identify three sites in one sample through elemental mass spectrometry detection with limits of detection of 1.2, 1.3, and 1.3 fmol, respectively. With the multisite cross-validation, we envision that this multiplex and sensitive detection platform may provide an effective strategy for SARS-CoV-2 fast screening with a high accuracy.