title: Induced effects of sodium ions on dopaminergic G-protein coupled receptors.
abstract: G-protein coupled receptors, the largest family of proteins in the human genome, are involved in many complex signal transduction pathways, typically activated by orthosteric ligand binding and subject to allosteric modulation. Dopaminergic receptors, belonging to the class A family of G-protein coupled receptors, are known to be modulated by sodium ions from an allosteric binding site, although the details of sodium effects on the receptor have not yet been described. In an effort to understand these effects, we performed microsecond scale all-atom molecular dynamics simulations on the dopaminergic D(2) receptor, finding that sodium ions enter the receptor from the extracellular side and bind at a deep allosteric site (Asp2.50). Remarkably, the presence of a sodium ion at this allosteric site induces a conformational change of the rotamer toggle switch Trp6.48 which locks in a conformation identical to the one found in the partially inactive state of the crystallized human beta(2) adrenergic receptor. This study provides detailed quantitative information about binding of sodium ions in the D(2) receptor and reports a possibly important sodium-induced conformational change for modulation of D(2) receptor function.
authors: Computer-Assisted Drug Design Laboratory, Research Unit on Biomedical Informatics, IMIM, Universitat Pompeu Fabra, Barcelona, Spain.
authors: Jana
authors: J
authors: Selent
authors: Ferran
authors: F
authors: Sanz
authors: Manuel
authors: M
authors: Pastor
authors: Gianni
authors: G
authors: De Fabritiis
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D006801:Humans; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry; D017448:Receptors, Dopamine D2 / Q000737:chemistry*; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry; D012964:Sodium / Q000737:chemistry*
chemical_list: D018343:Receptors, Adrenergic, beta-2; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled; D012964:Sodium