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Molecular basis of ligand dissociation in beta-adrenergic receptors
González Wong, Angel (Universitat Autònoma de Barcelona. Laboratori de Medicina Computacional)
Pérez-Acle, Tomás (Universidad de Chile. Center for Mathematical Modeling)
Pardo Carrasco, Leonardo (Universitat Autònoma de Barcelona. Laboratori de Medicina Computacional)
Deupí i Corral, Xavier (Paul Scherrer Institut (Suïssa))

Data: 2011
Resum: 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 β1 and β2ARs 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.
Drets: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Llengua: Anglès.
Document: article ; publishedVersion
Matèria: Beta-adrenergic receptors
Publicat a: PLoS one, Vol. 6, Issue 9 (September 2011) , p. e23815, ISSN 1932-6203

DOI: 10.1371/journal.pone.0023815
PMID: 21915263

9 p, 1.3 MB

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