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Investigation of the Entry Pathway and Molecular Nature of σ1 Receptor Ligands

The σ1 receptor (σ1-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 σ1-R’s physio-pathological and pharmacological importance, two of the most important f...

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Autores principales: Pascarella, Gianmarco, Antonelli, Lorenzo, Narzi, Daniele, Battista, Theo, Fiorillo, Annarita, Colotti, Gianni, Guidoni, Leonardo, Morea, Veronica, Ilari, Andrea
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10094450/
https://www.ncbi.nlm.nih.gov/pubmed/37047338
http://dx.doi.org/10.3390/ijms24076367
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author Pascarella, Gianmarco
Antonelli, Lorenzo
Narzi, Daniele
Battista, Theo
Fiorillo, Annarita
Colotti, Gianni
Guidoni, Leonardo
Morea, Veronica
Ilari, Andrea
author_facet Pascarella, Gianmarco
Antonelli, Lorenzo
Narzi, Daniele
Battista, Theo
Fiorillo, Annarita
Colotti, Gianni
Guidoni, Leonardo
Morea, Veronica
Ilari, Andrea
author_sort Pascarella, Gianmarco
collection PubMed
description The σ1 receptor (σ1-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 σ1-R’s physio-pathological and pharmacological importance, two of the most important features required to fully understand σ1-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 σ1-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 σ1-R endogenous ligand(s). Our MD simulations on human σ1-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 σ1-R from Xenopus laevis. Additionally, steroids were found to be among the preferred σ1-R ligands predicted by VS, and 16,17-didehydroprogesterone was shown by fluorescence titration to bind human σ1-R, with significantly higher affinity than the prototypic σ1-R ligand pridopidine in the same essay. These results support the hypothesis that steroids are among the most important physiological σ1-R ligands.
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spelling pubmed-100944502023-04-13 Investigation of the Entry Pathway and Molecular Nature of σ1 Receptor Ligands Pascarella, Gianmarco Antonelli, Lorenzo Narzi, Daniele Battista, Theo Fiorillo, Annarita Colotti, Gianni Guidoni, Leonardo Morea, Veronica Ilari, Andrea Int J Mol Sci Article The σ1 receptor (σ1-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 σ1-R’s physio-pathological and pharmacological importance, two of the most important features required to fully understand σ1-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 σ1-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 σ1-R endogenous ligand(s). Our MD simulations on human σ1-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 σ1-R from Xenopus laevis. Additionally, steroids were found to be among the preferred σ1-R ligands predicted by VS, and 16,17-didehydroprogesterone was shown by fluorescence titration to bind human σ1-R, with significantly higher affinity than the prototypic σ1-R ligand pridopidine in the same essay. These results support the hypothesis that steroids are among the most important physiological σ1-R ligands. MDPI 2023-03-28 /pmc/articles/PMC10094450/ /pubmed/37047338 http://dx.doi.org/10.3390/ijms24076367 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pascarella, Gianmarco
Antonelli, Lorenzo
Narzi, Daniele
Battista, Theo
Fiorillo, Annarita
Colotti, Gianni
Guidoni, Leonardo
Morea, Veronica
Ilari, Andrea
Investigation of the Entry Pathway and Molecular Nature of σ1 Receptor Ligands
title Investigation of the Entry Pathway and Molecular Nature of σ1 Receptor Ligands
title_full Investigation of the Entry Pathway and Molecular Nature of σ1 Receptor Ligands
title_fullStr Investigation of the Entry Pathway and Molecular Nature of σ1 Receptor Ligands
title_full_unstemmed Investigation of the Entry Pathway and Molecular Nature of σ1 Receptor Ligands
title_short Investigation of the Entry Pathway and Molecular Nature of σ1 Receptor Ligands
title_sort investigation of the entry pathway and molecular nature of σ1 receptor ligands
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10094450/
https://www.ncbi.nlm.nih.gov/pubmed/37047338
http://dx.doi.org/10.3390/ijms24076367
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