The binding sites for cocaine and dopamine in the dopamine transporter overlap

Nat Neurosci. 2008 Jul;11(7):780-9. doi: 10.1038/nn.2146. Epub 2008 Jun 22.


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 types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Binding Sites / drug effects
  • Binding, Competitive / drug effects
  • COS Cells
  • Chlorocebus aethiops
  • Cocaine / analogs & derivatives
  • Cocaine / metabolism*
  • Cocaine / pharmacokinetics
  • Cocaine / pharmacology
  • Dopamine / metabolism*
  • Dopamine / pharmacology
  • Dopamine Plasma Membrane Transport Proteins / chemistry
  • Dopamine Plasma Membrane Transport Proteins / genetics
  • Dopamine Plasma Membrane Transport Proteins / metabolism*
  • Dopamine Uptake Inhibitors / pharmacokinetics
  • Dose-Response Relationship, Drug
  • Models, Molecular
  • Mutagenesis, Site-Directed / methods
  • Protein Structure, Tertiary / drug effects
  • Protein Structure, Tertiary / physiology
  • Structure-Activity Relationship
  • Time Factors
  • Transfection / methods


  • Dopamine Plasma Membrane Transport Proteins
  • Dopamine Uptake Inhibitors
  • (1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester
  • Cocaine
  • Dopamine