A single glycine in extracellular loop 1 is determinant for pharmacological specificity of dopamine D2 and D3 receptors

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Tag-lite gives you a better understanding of drug-dependent receptor conformations


Subtype-selective agents for the dopamine D3 receptor (D3R) have been considered as potential medications for drug addiction and other neuropsychiatric disorders. Medicinal chemistry efforts have led to the discovery of 4-phenylpiperazine derivatives that are >100-fold selective for D3R over D2R, despite high sequence identity (78% in the transmembrane domain). Based on the recent crystal structure of D3R, we demonstrated that the 4-phenylpiperazine moiety in this class of D3R-selective compounds binds to the conserved orthosteric binding site whereas the extended aryl amide moiety is oriented towards a divergent secondary binding pocket (SBP). In an effort to further characterize molecular determinants of the selectivity of these compounds, we have modeled their binding modes in D3R and D2R by comparative ligand docking and molecular dynamics (MD) simulations. We found that the aryl amide moiety in the SBP differentially induces conformational changes in TM2 and EL1, which amplify the divergence of the SBP in D3R and D2R. Receptor chimera and site-directed mutagenesis studies were used to validate these binding modes and to identify a divergent glycine in EL1 as critical to D3R over D2R subtype-selectivity. A better understanding of drug-dependent receptor conformations such as these is key to the rational design of compounds targeting a specific receptor among closely related homologs, and may also lead to discovery of novel chemotypes that exploit subtle differences in protein conformations.


Mol Pharmacol. 2013;84(6):854-64.

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