Association of sigma‐1 receptor with dopamine transporter attenuates the binding of methamphetamine via distinct helix–helix interactions

Abstract

Dopamine transporter (DAT) and sigma‐1 receptor (σ1R) are potential therapeutic targets to reduce the psychostimulant effects induced by methamphetamine (METH). Interaction of σ1R 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 σ1R 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 σ1R and is more likely to act as an agonist. The relatively lower binding affinity of METH to σ1R supports the role of antagonists as inhibitors that protect against METH‐induced effects. We demonstrate that σ1R could bind to Drosophila melanogaster DAT (dDAT) through interactions with either the transmembrane helix α12 or α5 of dDAT. Our results showed that the truncated σ1R displays stronger association with dDAT than the full‐length σ1R. Although different helix–helix interactions between σ1R 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 α5 of dDAT. Together, the present study provides the first computational investigation on the molecular mechanism of coupling METH binding and the association of σ1R with dDAT.

Dual DAT and sigma receptor inhibitors attenuate cocaine effects on nucleus accumbens dopamine dynamics in rats

“…It is postulated that the neurochemical and behavioral differences in the observed effects of typical (cocaine-like) and atypical (rimcazole, SH 3-24, and JJC8-091) DAT inhibitors may reflect distinct preferences for binding to different DAT conformations. Typical DAT inhibitors have been shown to prefer or stabilize the outward-facing conformation of the dynamic DAT protein whereas atypical DAT inhibitors promote an inwardfacing DAT conformation (Abramyan et al, 2017;Loland et al, 2008Loland et al, , 2012Newman et al, 2019;Schmitt & Reith, 2010;Xu & Chen, 2021). Interestingly, exposure to a sigma-1 receptor agonist increased cocaine induced outward-facing DAT conformation, a process linked to the formation of sigma-1 receptor/DAT complexes (Hong et al, 2017;Sambo et al, 2017).…”

Structural Insights into the Human Mitochondrial Pyruvate Carrier Complexes

“…The CHARMM-GUI web server () was used to generate the input files used for MD simulations. − The protein was solvated by adding a 25 Å thick water layer (TIP3P water molecules) below and above the lipid bilayer. The salt concentration (NaCl) in each system was 0.15 M. The protein and lipid structures were represented with the CHARMM36m and CHARMM36 force field parameters, respectively. , The equilibration procedures were the same as used in our previous studies of membrane proteins. , Briefly, each system was first energy-minimized for 10,000 steps, followed by six stages of equilibration with the harmonic constraints exerted on lipid and protein heavy atoms. The force constants for the lipid head group were decreased from 1000 kJ/(mol nm 2 ) to 0, whereas the force constants for the protein backbone and sidechain (denoted as backbone/sidechain) were gradually decreased from 4000/2000 to 50/0 kJ/(mol nm 2 ) during the equilibration procedures.…”

“…34,35 The equilibration procedures were the same as used in our previous studies of membrane proteins. 36,37 Briefly, each system was first energy-minimized for 10,000 steps, followed by six stages of equilibration with the harmonic constraints exerted on lipid and protein heavy atoms. The force constants for the lipid head group were decreased from 1000 kJ/ (mol nm 2 ) to 0, whereas the force constants for the protein backbone and sidechain (denoted as backbone/sidechain) were gradually decreased from 4000/2000 to 50/0 kJ/(mol nm 2 ) during the equilibration procedures.…”