Reach Us +441414719275
All submissions of the EM system will be redirected to Online Manuscript Submission System. Authors are requested to submit articles directly to Online Manuscript Submission System of respective journal.

Abstract

Inter-helical Electrostatic Interaction and Rotameric Signatures in Activated Sphingosine-1-Phosphate Receptor 1

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.


Author(s):

Olaposi I Omotuyi, Hiroshi Ueda



Abstract | Full-Text | PDF

Share this  Facebook  Twitter  LinkedIn  Google+
Flyer image

Abstracted/Indexed in

  • Chemical Abstracts Service (CAS)
  • Index Copernicus
  • Google Scholar
  • China National Knowledge Infrastructure (CNKI)
  • Directory of Research Journal Indexing (DRJI)
  • WorldCat
  • Geneva Foundation for Medical Education and Research
  • Secret Search Engine Labs