Article abstract
Nature Structural & Molecular Biology 16, 652 - 657 (2009)
Published online: 10 May 2009 | Corrected online: 18 May 2009 | doi:10.1038/nsmb.1602
Antidepressant specificity of serotonin transporter suggested by three LeuT–SSRI structures
Zheng Zhou1,3, Juan Zhen2,3, Nathan K Karpowich1, Christopher J Law1, Maarten E A Reith2 & Da-Neng Wang1
Abstract
Sertraline and fluoxetine are selective serotonin re-uptake inhibitors (SSRIs) that are widely prescribed to treat depression. They exert their effects by inhibiting the presynaptic plasma membrane serotonin transporter (SERT). All SSRIs possess halogen atoms at specific positions, which are key determinants for the drugs' specificity for SERT. For the SERT protein, however, the structural basis of its specificity for SSRIs is poorly understood. Here we report the crystal structures of LeuT, a bacterial SERT homolog, in complex with sertraline, R-fluoxetine or S-fluoxetine. The SSRI halogens all bind to exactly the same pocket within LeuT. Mutation at this halogen-binding pocket (HBP) in SERT markedly reduces the transporter's affinity for SSRIs but not for tricyclic antidepressants. Conversely, when the only nonconserved HBP residue in both norepinephrine and dopamine transporters is mutated into that found in SERT, their affinities for all the three SSRIs increase uniformly. Thus, the specificity of SERT for SSRIs is dependent largely on interaction of the drug halogens with the protein's HBP.
- Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, Department of Cell Biology, New York University School of Medicine, New York, New York, USA.
- Departments of Psychiatry and of Pharmacology, New York University School of Medicine, New York, New York, USA.
- These authors contributed equally to this work.
Correspondence to: Maarten E A Reith2 e-mail: maarten.reith@med.nyu.edu
Correspondence to: Da-Neng Wang1 e-mail: wang@saturn.med.nyu.edu
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