The binding sites for cocaine and dopamine in the dopamine transporter overlap Academic Article uri icon

Overview

MeSH Major

  • Cocaine
  • Dopamine
  • Dopamine Plasma Membrane Transport Proteins

abstract

  • Cocaine is a widely abused substance with psychostimulant effects that are attributed to inhibition of the dopamine transporter (DAT). We present molecular models for DAT binding of cocaine and cocaine analogs constructed from the high-resolution structure of the bacterial transporter homolog LeuT. Our models suggest that the binding site for cocaine and cocaine analogs is deeply buried between transmembrane segments 1, 3, 6 and 8, and overlaps with the binding sites for the substrates dopamine and amphetamine, as well as for benztropine-like DAT inhibitors. We validated our models by detailed mutagenesis and by trapping the radiolabeled cocaine analog [3H]CFT in the transporter, either by cross-linking engineered cysteines or with an engineered Zn2+-binding site that was situated extracellularly to the predicted common binding pocket. Our data demonstrate the molecular basis for the competitive inhibition of dopamine transport by cocaine.

publication date

  • July 2008

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2692229

Digital Object Identifier (DOI)

  • 10.1038/nn.2146

PubMed ID

  • 18568020

Additional Document Info

start page

  • 780

end page

  • 9

volume

  • 11

number

  • 7