Abstract
The dopamine system, including five dopamine receptors (D1R to D5R), plays essential roles in the central nervous system (CNS) and ligands that activate dopamine receptors have been used to treat many neuronal disorders, yet no single structure of an agonist-bound dopamine receptor has been determined. Here we report the structures of human D3R in complex with an inhibitory G protein, either bound to a pan agonist, the Parkinson’s Disease drug pramipexole, or to a D3R-specific agonist, PD128907. The structures reveal distinct agonist binding modes from the antagonist-bound D3R structure and conformational signatures for ligand-induced receptor activation. Mutagenesis and homology modeling shed light into determinants of ligand specificity across dopamine receptors and the mechanism of selective G i protein coupling. Together with antagonist-bound structures, these results provide a template for the rational design of dopamine receptor-targeting ligands.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
