Insights from molecular dynamics: the binding site of cocaine in the dopamine transporter and permeation pathways of substrates in the leucine and dopamine transporters.

ABSTRACT: The dopamine transporter (DAT) facilitates the regulation of synaptic neurotransmitter levels. As a target for therapeutic and illicit psycho-stimulant drugs like antidepressants and cocaine, DAT has been studied intensively. Despite a wealth of mutational and physiological data regarding DAT, the structure remains unsolved and details of the transport mechanism, binding sites and conformational changes remain debated. A bacterial homolog of DAT, the leucine transporter (LeuT(Aa)) has been used as a template and framework for modeling and understanding DAT. Free energy profiles obtained from Multi-Configuration Thermodynamic Integration simulations allowed us to correctly identify the primary and secondary binding pockets of LeuT(Aa). A comparison of free energy profiles for dopamine and c

SUBMITTER: Merchant BA 

PROVIDER: S-EPMC3547672 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature