Molecular dynamics simulation of biased agonists at the dopamine D2 receptor suggests the mechanism of receptor functional selectivity

David Montgomery, Alexandra Campbell, Holli Joi Sullivan, Chun Wu

Research output: Contribution to journalArticle

Abstract

The dopamine D2 receptor (D2R) is the primary target for antipsychotic drugs. Besides schizophrenia, this receptor is linked to dementia, Parkinson’s disease, and depression. Recent studies have shown that β-arrestin biased agonists at this receptor treat schizophrenia with less side effects. Although the high resolution structure of this receptor exists, the mechanism of biased agonism at the receptor is unknown. In this study, dopamine, the endogenous unbiased G-protein agonist, MLS1547, a G-protein biased agonist, and UNC9975, a G-protein antagonist and a β-arrestin biased agonist, were docked to a homology model of the whole D2R including all flexible loops, and molecular dynamics simulations were conducted to study the potential mechanisms of biased agonism. Our thorough analysis on the protein–ligand interaction, secondary structure, tertiary structure, structure dynamics, and molecular switches of all three systems indicates that ligand binding to transmembrane 3 might be essential for G-protein recruitment, while ligand binding to transmembrane 6 might be essential for β-arrestin recruitment. Our analysis also suggests changes in both the secondary and the tertiary structures of TM5 and TM7, molecular switches and ICL3 flexibility are important in biased signaling. Communicated by Ramaswamy H. Sarma.

Original languageEnglish (US)
Pages (from-to)3206-3225
Number of pages20
JournalJournal of Biomolecular Structure and Dynamics
Volume37
Issue number12
DOIs
StatePublished - Aug 13 2019

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Dopamine D2 Receptors
Molecular Dynamics Simulation
Arrestin
GTP-Binding Proteins
Schizophrenia
Ligands
Molecular Structure
Antipsychotic Agents
Parkinson Disease
Dementia
Dopamine
Depression

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

Cite this

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abstract = "The dopamine D2 receptor (D2R) is the primary target for antipsychotic drugs. Besides schizophrenia, this receptor is linked to dementia, Parkinson’s disease, and depression. Recent studies have shown that β-arrestin biased agonists at this receptor treat schizophrenia with less side effects. Although the high resolution structure of this receptor exists, the mechanism of biased agonism at the receptor is unknown. In this study, dopamine, the endogenous unbiased G-protein agonist, MLS1547, a G-protein biased agonist, and UNC9975, a G-protein antagonist and a β-arrestin biased agonist, were docked to a homology model of the whole D2R including all flexible loops, and molecular dynamics simulations were conducted to study the potential mechanisms of biased agonism. Our thorough analysis on the protein–ligand interaction, secondary structure, tertiary structure, structure dynamics, and molecular switches of all three systems indicates that ligand binding to transmembrane 3 might be essential for G-protein recruitment, while ligand binding to transmembrane 6 might be essential for β-arrestin recruitment. Our analysis also suggests changes in both the secondary and the tertiary structures of TM5 and TM7, molecular switches and ICL3 flexibility are important in biased signaling. Communicated by Ramaswamy H. Sarma.",
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Molecular dynamics simulation of biased agonists at the dopamine D2 receptor suggests the mechanism of receptor functional selectivity. / Montgomery, David; Campbell, Alexandra; Sullivan, Holli Joi; Wu, Chun.

In: Journal of Biomolecular Structure and Dynamics, Vol. 37, No. 12, 13.08.2019, p. 3206-3225.

Research output: Contribution to journalArticle

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