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.
- Zheng Zhou
- Juan Zhen
- Da-Neng Wang
