Sphingosine-1 phosphate (S1P) receptor 1 (S1PR) is one of the receptors responsible for initiating intracellular signal transduction in response to extracellular signals encoded in Sphingosine-1 phosphate (S1P) and other related agonists. Using microsecond molecular dynamics simulation, rotameric (χ2) changes in the aromatic amino acids lining ligand-binding pocket, inter-helical electrostatic interaction, interaction between ligands (S1P and ML056) and selected extracellular regions of S1P have been studied. The data presented here strongly suggested that S1P-bound S1PR structure became active based on NPxxYmotif rmsd and dissociation of TM3/TM6 ionic lock as early as 300 ns while the apo- and ML056-bound S1PR were trapped in semi-active and inactive states respectively. Tyrosine 29 evolved agonist-dependent rotameric distribution while tryptophan 117 (W3.25), phenylalanine 210 (F5.47), tryptophan 269 (W6.48) and phenylalanine 273 (F6.52) exhibited activation-type signatures. Furthermore, while activation promoted TM1/TM4, TM2/TM7 and TM4/TM6 engagement, prior electrostatic engagements in TM3/TM4, TM3/TM6 and TM3/TM7 were dissolved. N-terminal-heptahelical bundle interaction is also compromised in inactive S1PR possibly due to reduced engagement of N-terminal residue such as lysine 34 and lysine 46. Ultimately, S1PR activation by class I agonist followed classical GPCR activation paradigm.
Olaposi I Omotuyi, Hiroshi Ueda
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