Structural biology: Blueprint for depression-treating SSRIs

The molecular structure of the human serotonin transporter (SERT), the target of many antidepressant drugs, is reported in a paper published online this week in Nature. The study describes the mechanism of action for two of the most widely prescribed selective serotonin reuptake inhibitors (SSRIs).

The neurotransmitter serotonin influences neurological processes, including sleep, hunger, mood and aggression. SSRIs are used to treat depression and anxiety disorders by blocking the reuptake of serotonin, thereby prolonging neurotransmitter signalling activity. Despite their widespread use, the molecular mechanism by which SSRIs inhibit SERT is not fully understood.

Eric Gouaux and colleagues used X-ray crystallography to obtain the structures of human SERT bound to two different antidepressants, (S)-citalopram and paroxetine. The authors determined that the antidepressants lock SERT in an ‘outward-open’ conformation and directly block serotonin from binding to this membrane protein. They suggest that their work provides a platform to design small molecules targeting the serotonin binding site, which could lead to the development of new SSRIs.

“Visualizing the detailed molecular structure of such a protein [SERT] could provide unprecedented opportunities to develop more selective and efficacious therapies for diseases such as depression,” write Marc Caron and Ulrik Gether in an accompanying News & Views article.