The mechanism of a high-affinity allosteric inhibitor of the serotonin transporter

Per Plenge, Ara M. Abramyan, Gunnar Sørensen, Arne Mørk, Pia Weikop, Ulrik Gether, Benny Bang-Andersen (), Lei Shi () and Claus J. Loland ()
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Per Plenge: University of Copenhagen
Ara M. Abramyan: Computational Chemistry and Molecular Biophysics Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse—Intramural Research Program, National Institutes of Health
Gunnar Sørensen: Lundbeck Research, H. Lundbeck A/S
Arne Mørk: Lundbeck Research, H. Lundbeck A/S
Pia Weikop: University of Copenhagen
Ulrik Gether: University of Copenhagen
Benny Bang-Andersen: Lundbeck Research, H. Lundbeck A/S
Lei Shi: Computational Chemistry and Molecular Biophysics Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse—Intramural Research Program, National Institutes of Health
Claus J. Loland: University of Copenhagen

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract The serotonin transporter (SERT) terminates serotonin signaling by rapid presynaptic reuptake. SERT activity is modulated by antidepressants, e.g., S-citalopram and imipramine, to alleviate symptoms of depression and anxiety. SERT crystal structures reveal two S-citalopram binding pockets in the central binding (S1) site and the extracellular vestibule (S2 site). In this study, our combined in vitro and in silico analysis indicates that the bound S-citalopram or imipramine in S1 is allosterically coupled to the ligand binding to S2 through altering protein conformations. Remarkably, SERT inhibitor Lu AF60097, the first high-affinity S2-ligand reported and characterized here, allosterically couples the ligand binding to S1 through a similar mechanism. The SERT inhibition by Lu AF60097 is demonstrated by the potentiated imipramine binding and increased hippocampal serotonin level in rats. Together, we reveal a S1-S2 coupling mechanism that will facilitate rational design of high-affinity SERT allosteric inhibitors.

Date: 2020
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DOI: 10.1038/s41467-020-15292-y

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