Binding site residues control inhibitor selectivity in the human norepinephrine transporter but not in the human dopamine transporter.

ABSTRACT: The transporters for norepinephrine and dopamine (NET and DAT, respectively) constitute the molecular targets for recreational drugs and therapeutics used in the treatment of psychiatric disorders. Despite a strikingly similar amino acid sequence and predicted topology between these transporters, some inhibitors display a high degree of selectivity between NET and DAT. Here, a systematic mutational analysis of non-conserved residues within the extracellular entry pathway and the high affinity binding site in NET and DAT was performed to examine their role for selective inhibitor recognition. Changing the six diverging residues in the central binding site of NET to the complementary residues in DAT transferred a DAT-like pharmacology to NET, showing that non-conserved binding site residues

SUBMITTER: Andersen J 

PROVIDER: S-EPMC4621520 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature