1 Medicinal Chemistry Research, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet2 Computational and RNA Biology, Department of Biology, Faculty of Science, Københavns Universitet3 Department of Drug Design and Pharmacology, Faculty of Pharmaceutical Sciences, Københavns Universitet4 Department of Drug Design and Pharmacology, University of Copenhagen5 Department of Drug Design and Pharmacology, Faculty of Pharmaceutical Sciences, Københavns Universitet6 Medicinal Chemistry Research, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet7 Computational and RNA Biology, Department of Biology, Faculty of Science, Københavns Universitet
mutational studies of the S<sub>1</sub> substrate binding pocket
The serotonin transporter (SERT) and the norepinephrine transporter (NET) are sodium-dependent neurotransmitter transporters responsible for reuptake of released serotonin and norepinephrine, respectively, into nerve terminals in the brain. A wide range of inhibitors of SERT and NET are used as treatment of depression and anxiety disorders or as psychostimulant drugs of abuse. Despite their clinical importance, the molecular mechanisms by which various types of antidepressant drugs bind and inhibit SERT and NET are still elusive for the majority of the inhibitors, including the molecular basis for SERT/NET selectivity. Mutational analyses have suggested that a central substrate binding site (denoted the S1 pocket) also harbors an inhibitor binding site. In this study, we determine the effect of mutating six key S1 residues in human SERT (hSERT) and NET (hNET) on the potency of 15 prototypical SERT/NET inhibitors belonging to different drug classes. Analysis of the resulting drug sensitivity profiles provides novel information on drug binding modes in hSERT and hNET and identifies specific S1 residues as important molecular determinants for inhibitor potency and hSERT/hNET selectivity.
Journal of Biological Chemistry, 2012, Vol 287, Issue 52, p. 43694-43707
Animals; Antidepressive Agents; Binding Sites; COS Cells; Cercopithecus aethiops; Humans; Molecular Dynamics Simulation; Mutation; Norepinephrine Plasma Membrane Transport Proteins; Peptide Mapping; Protein Binding; Serotonin Plasma Membrane Transport Proteins