Molecular basis of ligand dissociation in β-adrenergic receptors.

The important and diverse biological functions of β-adrenergic receptors (βARs) have promoted the search for compounds to stimulate or inhibit their activity. In this regard, unraveling the molecular basis of ligand binding/unbinding events is essential to understand the pharmacological properties o...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Angel González, Tomas Perez-Acle, Leonardo Pardo, Xavier Deupi
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bff93babe41e46a8830e3868ef289cff
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:bff93babe41e46a8830e3868ef289cff
record_format	dspace
spelling	oai:doaj.org-article:bff93babe41e46a8830e3868ef289cff2021-11-18T06:46:35ZMolecular basis of ligand dissociation in β-adrenergic receptors.1932-620310.1371/journal.pone.0023815https://doaj.org/article/bff93babe41e46a8830e3868ef289cff2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21915263/?tool=EBIhttps://doaj.org/toc/1932-6203The important and diverse biological functions of β-adrenergic receptors (βARs) have promoted the search for compounds to stimulate or inhibit their activity. In this regard, unraveling the molecular basis of ligand binding/unbinding events is essential to understand the pharmacological properties of these G protein-coupled receptors. In this study, we use the steered molecular dynamics simulation method to describe, in atomic detail, the unbinding process of two inverse agonists, which have been recently co-crystallized with β(1) and β(2)ARs subtypes, along four different channels. Our results indicate that this type of compounds likely accesses the orthosteric binding site of βARs from the extracellular water environment. Importantly, reconstruction of forces and energies from the simulations of the dissociation process suggests, for the first time, the presence of secondary binding sites located in the extracellular loops 2 and 3 and transmembrane helix 7, where ligands are transiently retained by electrostatic and Van der Waals interactions. Comparison of the residues that form these new transient allosteric binding sites in both βARs subtypes reveals the importance of non-conserved electrostatic interactions as well as conserved aromatic contacts in the early steps of the binding process.Angel GonzálezTomas Perez-AcleLeonardo PardoXavier DeupiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 9, p e23815 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Angel González Tomas Perez-Acle Leonardo Pardo Xavier Deupi Molecular basis of ligand dissociation in β-adrenergic receptors.
description	The important and diverse biological functions of β-adrenergic receptors (βARs) have promoted the search for compounds to stimulate or inhibit their activity. In this regard, unraveling the molecular basis of ligand binding/unbinding events is essential to understand the pharmacological properties of these G protein-coupled receptors. In this study, we use the steered molecular dynamics simulation method to describe, in atomic detail, the unbinding process of two inverse agonists, which have been recently co-crystallized with β(1) and β(2)ARs subtypes, along four different channels. Our results indicate that this type of compounds likely accesses the orthosteric binding site of βARs from the extracellular water environment. Importantly, reconstruction of forces and energies from the simulations of the dissociation process suggests, for the first time, the presence of secondary binding sites located in the extracellular loops 2 and 3 and transmembrane helix 7, where ligands are transiently retained by electrostatic and Van der Waals interactions. Comparison of the residues that form these new transient allosteric binding sites in both βARs subtypes reveals the importance of non-conserved electrostatic interactions as well as conserved aromatic contacts in the early steps of the binding process.
format	article
author	Angel González Tomas Perez-Acle Leonardo Pardo Xavier Deupi
author_facet	Angel González Tomas Perez-Acle Leonardo Pardo Xavier Deupi
author_sort	Angel González
title	Molecular basis of ligand dissociation in β-adrenergic receptors.
title_short	Molecular basis of ligand dissociation in β-adrenergic receptors.
title_full	Molecular basis of ligand dissociation in β-adrenergic receptors.
title_fullStr	Molecular basis of ligand dissociation in β-adrenergic receptors.
title_full_unstemmed	Molecular basis of ligand dissociation in β-adrenergic receptors.
title_sort	molecular basis of ligand dissociation in β-adrenergic receptors.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/bff93babe41e46a8830e3868ef289cff
work_keys_str_mv	AT angelgonzalez molecularbasisofliganddissociationinbadrenergicreceptors AT tomasperezacle molecularbasisofliganddissociationinbadrenergicreceptors AT leonardopardo molecularbasisofliganddissociationinbadrenergicreceptors AT xavierdeupi molecularbasisofliganddissociationinbadrenergicreceptors
_version_	1718424442900578304

Molecular basis of ligand dissociation in β-adrenergic receptors.

Ejemplares similares