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Research ArticleArticle

Molecular Basis for Selective Serotonin Reuptake Inhibition by the Antidepressant Agent Fluoxetine (Prozac)

Jacob Andersen, Nicolai Stuhr-Hansen, Linda Grønborg Zachariassen, Heidi Koldsø, Birgit Schiøtt, Kristian Strømgaard and Anders S. Kristensen
Molecular Pharmacology May 2014, 85 (5) 703-714; DOI: https://doi.org/10.1124/mol.113.091249
Jacob Andersen
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark (J.A., N.S.-H., L.G.Z., K.S., A.S.K.); and Center for Insoluble Structures (inSPIN) and Interdisciplinary Nanoscience Center (iNANO), Department of Chemistry, Aarhus University, Aarhus, Denmark (H.K., B.S.)
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Nicolai Stuhr-Hansen
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark (J.A., N.S.-H., L.G.Z., K.S., A.S.K.); and Center for Insoluble Structures (inSPIN) and Interdisciplinary Nanoscience Center (iNANO), Department of Chemistry, Aarhus University, Aarhus, Denmark (H.K., B.S.)
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Linda Grønborg Zachariassen
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark (J.A., N.S.-H., L.G.Z., K.S., A.S.K.); and Center for Insoluble Structures (inSPIN) and Interdisciplinary Nanoscience Center (iNANO), Department of Chemistry, Aarhus University, Aarhus, Denmark (H.K., B.S.)
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Heidi Koldsø
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark (J.A., N.S.-H., L.G.Z., K.S., A.S.K.); and Center for Insoluble Structures (inSPIN) and Interdisciplinary Nanoscience Center (iNANO), Department of Chemistry, Aarhus University, Aarhus, Denmark (H.K., B.S.)
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Birgit Schiøtt
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark (J.A., N.S.-H., L.G.Z., K.S., A.S.K.); and Center for Insoluble Structures (inSPIN) and Interdisciplinary Nanoscience Center (iNANO), Department of Chemistry, Aarhus University, Aarhus, Denmark (H.K., B.S.)
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Kristian Strømgaard
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark (J.A., N.S.-H., L.G.Z., K.S., A.S.K.); and Center for Insoluble Structures (inSPIN) and Interdisciplinary Nanoscience Center (iNANO), Department of Chemistry, Aarhus University, Aarhus, Denmark (H.K., B.S.)
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Anders S. Kristensen
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark (J.A., N.S.-H., L.G.Z., K.S., A.S.K.); and Center for Insoluble Structures (inSPIN) and Interdisciplinary Nanoscience Center (iNANO), Department of Chemistry, Aarhus University, Aarhus, Denmark (H.K., B.S.)
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Abstract

Inhibitors of the serotonin transporter (SERT) are widely used antidepressant agents, but the structural mechanism for inhibitory activity and selectivity over the closely related norepinephrine transporter (NET) is not well understood. Here we use a combination of chemical, biological, and computational methods to decipher the molecular basis for high-affinity recognition in SERT and selectivity over NET for the prototypical antidepressant drug fluoxetine (Prozac; Eli Lilly, Indianapolis, IN). We show that fluoxetine binds within the central substrate site of human SERT, in agreement with recent X-ray crystal structures of LeuBAT, an engineered monoamine-like version of the bacterial amino acid transporter LeuT. However, the binding orientation of fluoxetine is reversed in our experimentally supported model compared with the LeuBAT structures, emphasizing the need for careful experimental verification when extrapolating findings from crystal structures of bacterial transporters to human relatives. We find that the selectivity of fluoxetine and nisoxetine, a NET selective structural congener of fluoxetine, is controlled by residues in different regions of the transporters, indicating a complex mechanism for selective recognition of structurally similar compounds in SERT and NET. Our findings add important new information on the molecular basis for SERT/NET selectivity of antidepressants, and provide the first assessment of the potential of LeuBAT as a model system for antidepressant binding in human transporters, which is essential for future structure-based drug development of antidepressant drugs with fine-tuned transporter selectivity.

Footnotes

    • Received December 20, 2013.
    • Accepted February 10, 2014.
  • ↵1 Current affiliation: Department of Chemistry, University of Copenhagen, Copenhagen, Denmark.

  • ↵2 Current affiliation: Department of Biochemistry, University of Oxford, Oxford, United Kingdom.

  • This work was supported by the Lundbeck Foundation, the Danish National Research Foundation (DNRF59), and the Danish Council for Independent Research, Natural Sciences.

  • dx.doi.org/10.1124/mol.113.091249.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 85 (5)
Molecular Pharmacology
Vol. 85, Issue 5
1 May 2014
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Research ArticleArticle

The Fluoxetine Binding Site in Human SERT

Jacob Andersen, Nicolai Stuhr-Hansen, Linda Grønborg Zachariassen, Heidi Koldsø, Birgit Schiøtt, Kristian Strømgaard and Anders S. Kristensen
Molecular Pharmacology May 1, 2014, 85 (5) 703-714; DOI: https://doi.org/10.1124/mol.113.091249

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Research ArticleArticle

The Fluoxetine Binding Site in Human SERT

Jacob Andersen, Nicolai Stuhr-Hansen, Linda Grønborg Zachariassen, Heidi Koldsø, Birgit Schiøtt, Kristian Strømgaard and Anders S. Kristensen
Molecular Pharmacology May 1, 2014, 85 (5) 703-714; DOI: https://doi.org/10.1124/mol.113.091249
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