Substrate and drug binding sites in LeuT.
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.
Nyola
Ajeeta
A
Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, and Department of Cell Biology, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.
Karpowich
Nathan K
NK
Zhen
Juan
J
Marden
Jennifer
J
Reith
Maarten E
ME
Wang
Da-Neng
DN
D026905:Amino Acid Transport Systems / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D006801:Humans; D007930:Leucine / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity
D026905:Amino Acid Transport Systems; D004364:Pharmaceutical Preparations; D050480:Plasma Membrane Neurotransmitter Transport Proteins; D007930:Leucine