Induced Effects of Sodium Ions on Dopaminergic G-Protein Coupled Receptors

• Published in: PLoS computational biology Vol. 6; no. 8; p. e1000884
• Main Authors: Selent, Jana, Sanz, Ferran, Pastor, Manuel, De Fabritiis, Gianni
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.08.2010; Public Library of Science (PLoS)
• Subjects: Allosteric Regulation; Allosteric Site; Biochemistry; Biophysics; Cell receptors; Chemical properties; Computational Biology; Computational Biology/Molecular Dynamics; Conformation; Genoma humà; Health aspects; Humans; Molecular Dynamics Simulation; Properties; Protein binding; Protein Conformation; Proteins; Proteïnes; Receptors, Adrenergic, beta-2 - chemistry; Receptors, Dopamine D2 - chemistry; Receptors, G-Protein-Coupled - chemistry; Signal transduction; Simulation; Sodium; Sodium - chemistry; Sodium compounds; Studies; Spain; Sodium; Allosteric Regulation; Humans; Allosteric Site; Receptors, Dopamine D2; Receptors, G-Protein-Coupled; Protein Conformation; Receptors, Adrenergic, beta-2; Molecular Dynamics Simulation
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1000884

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.