A Molecular Basis for Selective Antagonist Destabilization of Dopamine D3 Receptor Quaternary Organization

Scientific Reports
Sara MarsangoGraeme Milligan

Abstract

The dopamine D3 receptor (D3R) is a molecular target for both first-generation and several recently-developed antipsychotic agents. Following stable expression of this mEGFP-tagged receptor, Spatial Intensity Distribution Analysis indicated that a substantial proportion of the receptor was present within dimeric/oligomeric complexes and that increased expression levels of the receptor favored a greater dimer to monomer ratio. Addition of the antipsychotics, spiperone or haloperidol, resulted in re-organization of D3R quaternary structure to promote monomerization. This action was dependent on ligand concentration and reversed upon drug washout. By contrast, a number of other antagonists with high affinity at the D3R, did not alter the dimer/monomer ratio. Molecular dynamics simulations following docking of each of the ligands into a model of the D3R derived from the available atomic level structure, and comparisons to the receptor in the absence of ligand, were undertaken. They showed that, in contrast to the other antagonists, spiperone and haloperidol respectively increased the atomic distance between reference α carbon atoms of transmembrane domains IV and V and I and II, both of which provide key interfaces for D3R dimeriza...Continue Reading

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Citations

Jun 20, 2019·International Journal of Molecular Sciences·Elise WoutersChristophe P Stove
Apr 17, 2019·International Journal of Molecular Sciences·Elise WoutersChristophe Stove
Oct 22, 2020·Science Signaling·Rudy ToneattiJavier González-Maeso
Dec 4, 2020·The Journal of Biological Chemistry·Richard J WardGraeme Milligan
Jan 19, 2021·The Journal of Biological Chemistry·Richard J WardGraeme Milligan
Aug 15, 2018·Journal of Medicinal Chemistry·Eric A WoldJia Zhou

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Methods Mentioned

BETA
Fluorescence
confocal microscopy
fluorescence recovery after photobleaching
PCR
saturation binding

Software Mentioned

SpIDA
Autodeblur
Modeller
Autodock Vina
GROMACS
Action
Autovisualise
Metamorph
Mass
Graphpad Prism

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