The s1 receptor (s1-R) is an enigmatic endoplasmic reticulum resident transmembrane protein implicated in a variety of central nervous system disorders and whose agonists have neuroprotective activity. In spite of s1-R's physio-pathological and pharmacological importance, two of the most important features required to fully understand s1-R function, namely the receptor endogenous ligand(s) and the molecular mechanism of ligand access to the binding site, have not yet been unequivocally determined. In this work, we performed molecular dynamics (MD) simulations to help clarify the potential route of access of ligand(s) to the s1-R binding site, on which discordant results had been reported in the literature. Further, we combined computational and experimental procedures (i.e., virtual screening (VS), electron density map fitting and fluorescence titration experiments) to provide indications about the nature of s1-R endogenous ligand(s). Our MD simulations on human s1-R suggested that ligands access the binding site through a cavity that opens on the protein surface in contact with the membrane, in agreement with previous experimental studies on s1-R from Xenopus laevis. Additionally, steroids were found to be among the preferred s1-R ligands predicted by VS, and 16,17-didehydroprogesterone was shown by fluorescence titration to bind human s1-R, with significantly higher affinity than the prototypic s1-R ligand pridopidine in the same essay. These results support the hypothesis that steroids are among the most important physiological s1-R ligands.
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