Antidepressants at work

Abstract

Structures of the serotonin transporter protein SERT in complex with two different antidepressants shed light on how these drugs act, and point to possible targets for future drug development. See Article p.334 Serotonin modulates the activity of the central nervous system, as well as many other processes throughout the body. These authors have solved X-ray structures of the human serotonin transporter (SERT) in complex with the selective serotonin reuptake inhibitors (SSRIs) (S)-citalopram and paroxetine — two of the most widely prescribed antidepressants. The resulting structures reveal that the antidepressants lock the protein in an outward-open conformation, and directly block the entry of serotonin into its binding site. A previously unknown allosteric site is seen in the extracellular vestibule; binding of ligands to this site prevents dissociation from the central site, establishing a mechanism of antidepressant action in SERT and pointing the way for future drug design.