title: Activation mechanisms of the first sphingosine-1-phosphate receptor.
abstract: Activation of the first sphingosine-1-phosphate receptor (S1PR1) promotes permeability of the blood brain barrier, astrocyte and neuronal protection, and lymphocyte egress from secondary lymphoid tissues. Although an agonist often activates the S1PR1, the receptor exhibits high levels of basal activity. In this study, we performed long-timescale molecular dynamics and accelerated molecular dynamics (aMD) simulations to investigate activation mechanisms of the ligand-free (apo) S1PR1. In the aMD enhanced sampling simulations, we observed four independent events of activation, which is characterized by close interaction between Y3117.53and Y2215.58and increased distance between the intracellular ends of transmembrane (TM) helices 3 and 6. Although TM helices TM3, TM6, TM5 and, TM7 are associated with GPCR activation, we discovered that their movements are not necessarily correlated during activation. Instead, TM5 showed a decreased correlation with each of these regions during activation. During activation of the apo receptor, Y2215.58and Y3117.53became more solvated, because a water channel formed in the intracellular pocket. Additionally, a lipid molecule repeatedly entered the receptor between the extracellular ends of TM1 and TM7, providing important insights into the pathway of ligand entry into the S1PR1.
authors.affiliation: Department of Pharmacology, University of California at San Diego, La Jolla, California, 92093.
authors.forename: Alisha D
authors.initials: AD
authors.lastname: Caliman
authors.affiliation: Department of Pharmacology, University of California at San Diego, La Jolla, California, 92093.|Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California, 92093.
authors.forename: Yinglong
authors.initials: Y
authors.lastname: Miao
authors.affiliation: Department of Pharmacology, University of California at San Diego, La Jolla, California, 92093.|Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California, 92093.|Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California, 92093.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D003198:Computer Simulation; D006801:Humans; D056004:Molecular Dynamics Simulation; D017433:Protein Structure, Secondary; D049349:Receptors, Lysosphingolipid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors
chemical_list: D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; D000081025:Sphingosine-1-Phosphate Receptors
keywords: GPCR; S1PR1; activation; molecular dynamics