At last, scientists solve structure of protein that antidepressants target

Drug designers have long been synthesizing antidepressant compounds capable of interfering with the human serotonin transporter, or SERT. But much of what scientists know about SERT’s structure comes from studies of related proteins from other species, such as the bacterial leucine transporter and the fruit fly dopamine transporter.

Now, the structure of SERT itself has been solved, a feat that could help drug designers improve antidepressants. Eric Gouaux, Jonathan A. Coleman, and Evan M. Green of Oregon Health & Science University report crystal structures of human SERT bound to the antidepressants (S)-citalopram (Lexapro) or paroxetine (Paxil) (Nature 2016, DOI: 10.1038/nature17629). They’re the first crystal structures of a human neurotransmitter transporter.

In the body, SERT sits in the membrane of neurons that feed into a nerve cell junction, or synapse. Its job is to remove excess serotonin—a neurotransmitter associated with feelings of happiness—from the synapse and transport it back inside the neuron. When SERT gets blocked by an antidepressant, however, serotonin stays in the synapse, continuing to exert its feel-good effects.

To determine SERT’s structure, the Oregon team first had to find a form of the transporter that would crystallize. “The human transporter is remarkably unstable after you extract it from the membrane,” Gouaux says. “The crucial aspect of this study was discovering a few sites in the transporter that we could mutate and dramatically increase the thermal stability” while retaining SERT’s normal antidepressant binding, he adds. The team was able to crystallize a form of SERT with three mutations, but it wasn’t an active transporter.

The structures that the researchers determined from this inactive transporter not only pinpointed the location of the main binding site, but they also pinpointed a secondary, allosteric binding site that, when occupied, blocks release of the antidepressant from the main site. In the citalopram complex, the antidepressant bound to both the central binding site and to the allosteric site. Paroxetine, which has only weak allosteric activity, didn’t bind to the secondary site.

The structures show that the antidepressants work by occupying the serotonin binding site and preventing the transporter from switching from one conformation to another. An antidepressant acts “like a wedge in a door,” Gouaux says. “It completely blocks the outer door from closing and will not allow the transporter to reopen to the inside.”

This transporter structure might provide a map for discovering new drugs, especially ones that target the allosteric site, says Claus J. Løland, who studies neurotransmitter transporters at the University of Copenhagen. “Binding to this site might have different therapeutic perspectives than classical competitive inhibition.”

Løland calls the work impressive and groundbreaking. “Gouaux’s group has moved the field of transporter structures from bacteria to man within a decade, give or take, and with a minimum of modifications,” he says. “One could think this makes all transporter structures published prior to this obsolete, but that would be an overstatement because we still have most insights to protein function from the bacterial transporters.”

This article has been translated into Spanish by Divulgame.org and can be found here.