Portal de Periódicos da CAPES

Antidepressant specificity of serotonin transporter suggested by three LeuT–SSRI structures

2009; Nature Portfolio; Volume: 16; Issue: 6 Linguagem: Inglês

10.1038/nsmb.1602

1545-9993

Zheng Zhou, Juan Zhen, Nathan K. Karpowich, Christopher J. Law, Maarten E. A. Reith, Da‐Neng Wang,

Neurotransmitter Receptor Influence on Behavior

Sertraline (Zoloft) and fluoxetine (Prozac) are selective serotonin-reuptake inhibitors (SSRIs) that are widely prescribed to treat depression. They bind to the presynaptic plasma membrane serotonin transporter (SERT) and inhibit serotonin uptake. Both these drugs possess halogen atoms, but the structural basis for the specificity of SERT for these inhibitors was not known. Zhou et al. now report the crystal structure of LeuT, a bacterial SERT homolog in complex with three different SSRIs. The halogen atoms of all three bind within exactly the same pocket of LeuT, and mutations within this pocket in SERT markedly reduce the transporter's affinity for SSRIs but not for tricyclic antidepressants. 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.