Issue Date: August 13, 2007
AN IMPORTANT CLASS of drugs-tricyclic antidepressants (TCAs)—binds in a surprising place. That finding, based on studies with a bacterial protein, could influence the design of new drugs for depression.
According to two new studies, TCAs seal off a molecular passageway in a bacterial counterpart of human neurotransmitter transporter proteins (Nature, DOI: 10.1038/nature06038 and Science, DOI: 10.1126/science.1147614). The work indicates a molecular mechanism of action for this compound class.
Since the 1950s, TCAs such as desipramine (Norpramin and Pertofrane) have been prescribed to treat symptoms of depression. They prevent reuptake of serotonin and norepinephrine by binding to corresponding membrane-spanning neurotransmitter transporter proteins.
Although TCAs' protein targets are known, their binding site on these targets has remained unidentified, says structural biologist Da-Neng Wang of New York University's School of Medicine, who led the Science study with NYU pharmacologist Maarten E. A. Reith. TCAs may compete with the naturally occurring substrate for an identical binding site, or they may bind at a site distal to the natural substrate's binding site.
The new structural work—structures of the bacterial transporter with three different TCAs solved by Eric Gouaux and colleagues at Oregon Health & Science University and Reith and Wang's structure of the same transporter with desipramine—demonstrates that TCAs do not interact at the substrate's binding site. Rather, they bind outside the transporter's extracellular gate. Extensive structural and kinetic data in the Gouaux group's Nature study show that TCA binding closes this gate by stabilizing a key salt bridge that hinders substrate release into the cell.
Reith and Wang also tweaked the presumed TCA binding sites of human transporters and followed changes in desipramine inhibition. These studies support the idea that the TCA binding site may be conserved in human neurotransmitter transporters, they say.
Yale University pharmacologist Gary Rudnick suggests caution in extending these studies' findings, based on bacterial transporters, to mammalian transporters. He previously showed that a TCA competes with serotonin for binding to the human serotonin transporter. In contrast, Gouaux's functional studies indicate that TCAs do not compete with substrate for binding to the bacterial transporter.
In recent years, TCAs have been supplanted by highly selective serotonin reuptake inhibitors such as fluoxetine (Prozac), which interact with the same class of transporters. Medicinal chemists could use the insights gleaned from the current studies in designing new leads for fighting depression, according to chemist Dennis Dougherty of Caltech. "For an undeniably important target class, we have our first glimpse of where an important class of drugs binds," he adds.
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