Substrate and drug binding sites in LeuT

Curr Opin Struct Biol. 2010 Aug;20(4):415-22. doi: 10.1016/ Epub 2010 Jun 16.


LeuT is a member of the neurotransmitter/sodium symporter family, which includes the neuronal transporters for serotonin, norepinephrine, and dopamine. The original crystal structure of LeuT shows a primary leucine-binding site at the center of the protein. LeuT is inhibited by different classes of antidepressants that act as potent inhibitors of the serotonin transporter. The newly determined crystal structures of LeuT-antidepressant complexes provide opportunities to probe drug binding in the serotonin transporter, of which the exact position remains controversial. Structure of a LeuT-tryptophan complex shows an overlapping binding site with the primary substrate site. A secondary substrate binding site was recently identified, where the binding of a leucine triggers the cytoplasmic release of the primary substrate. This two binding site model presents opportunities for a better understanding of drug binding and the mechanism of inhibition for mammalian transporters.

Publication types

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

MeSH terms

  • Amino Acid Transport Systems / chemistry*
  • Amino Acid Transport Systems / metabolism*
  • Animals
  • Binding Sites
  • Humans
  • Leucine / metabolism*
  • Pharmaceutical Preparations / metabolism*
  • Plasma Membrane Neurotransmitter Transport Proteins / chemistry
  • Plasma Membrane Neurotransmitter Transport Proteins / metabolism
  • Substrate Specificity


  • Amino Acid Transport Systems
  • Pharmaceutical Preparations
  • Plasma Membrane Neurotransmitter Transport Proteins
  • Leucine