Association Of Sigma-1 Receptor With Dopamine Transporter Attenuates The Binding Of Methamphetamine Via Distinct Helix-Helix Interactions

Dopamine transporter (DAT) and sigma-1 receptor (sigma 1R) are potential therapeutic targets to reduce the psychostimulant effects induced by methamphetamine (METH). Interaction of sigma 1R with DAT could modulate the binding of METH, but the molecular basis of the association of the two transmembrane proteins and how their interactions mediate the binding of METH to DAT or sigma 1R remain unclear. Here, we characterize the protein-ligand and protein-protein interactions at a molecular level by various theoretical approaches. The present results show that METH adopts a different binding pose in the binding pocket of sigma 1R and is more likely to act as an agonist. The relatively lower binding affinity of METH to sigma 1R supports the role of antagonists as inhibitors that protect against METH-induced effects. We demonstrate that sigma 1R could bind to Drosophila melanogaster DAT (dDAT) through interactions with either the transmembrane helix alpha 12 or alpha 5 of dDAT. Our results showed that the truncated sigma 1R displays stronger association with dDAT than the full-length sigma 1R. Although different helix-helix interactions between sigma 1R and dDAT lead to distinct effects on the dynamics of individual protein, both associations attenuate the binding affinity of METH to dDAT, particularly in the interactions with the helix alpha 5 of dDAT. Together, the present study provides the first computational investigation on the molecular mechanism of coupling METH binding and the association of sigma 1R with dDAT.