Antidepressants and their targets: binding at an atomic level
March 29, 2018
Story and photo by Erika Cuellar
The OHSU School of Medicine's Paper of the Month for March 2018 is "Structural Basis for Recognition of Diverse Antidepressants by the Human Serotonin Transporter" published in Nature Structural & Molecular Biology.
Authors Jonathan A. Coleman, Ph.D., and Eric Gouaux, Ph.D.,* use x-ray crystallography and electron density modeling to determine the structural interactions of antidepressants bound to serotonin transporter (SERT).
SERT is a membrane protein that resides in the presynaptic neurons and acts to recycle the neurotransmitter serotonin from the synapse into neurons. Serotonin is a chemical messenger that acts as a neurotransmitter, carrying signals between neurons.
Serotonin signaling controls many aspects of human behavior, including memory, learning, sleep, hunger, pain, sexual function and mood. SERT is the target of antidepressant and anti-anxiety drugs that are also referred to as selective serotonin reuptake inhibitors (SSRIs) because they bind to the transporter and inhibit neurotransmitter recycling by blocking binding of serotonin. Antidepressants are a class of drugs that bind the outward state of the transporter to a primary site with high affinity; however, due to their chemical and structural diversity, it is unclear how this occurs at an atomic level.
Previous research by Dr. Coleman and the Gouaux lab has shed light on the mechanism of antidepressant action on SERT. For example, the research team has solved x-ray structures of SERT in complex with the antidepressants, paroxetine and S-citalopram. These drugs can also bind to the outward-open state of the transporter as predicted by functional studies of SERT and structures of related neurotransmitter transporters. In addition, they have identified the location of an allosteric site for S-citalopram. Binding of the antidepressant to the second site sterically hinders ligand unbinding from the central site, providing an explanation for its action as an allosteric ligand.
Binding of other antidepressants to SERT
Recently, Drs. Coleman and Gouaux discovered that the antidepressant drugs sertraline and fluvoxamine also bind to the primary site in the outward facing state of the transporter and prevent serotonin binding.
In contrast to S-citalopram, they were unable to detect binding of sertraline and fluvoxamine to the second site. By comparing drug binding of these structures to their previous work, the authors were able to explain how the transporter can orchestrate binding of chemically diverse inhibitors and potentially mediate SERT selectivity.
"It is really remarkable that these apparently very different drugs all interact with their target, the serotonin transporter, in essentially the same way", said Mary Heinricher, Ph.D., associate dean for basic research, OHSU School of Medicine.
Next steps and future direction
With depression being reported as the leading cause of disability in the United States among people ages 15-44 (World Health Organization 2018), it is not surprising that the need for effective treatments has also increased. Antidepressants are among the most commonly prescribed medications and are used for the treatment of depression; however the molecular features that cause the drug to be recognized are not well understood. Furthermore, antidepressants can cause a wide range of side effects, including sexual dysfunction, insomnia, nausea, headaches and diarrhea.
Results from this study
can potentially provide a pathway for the development of new classes of
antidepressants that better treat depression while limiting side
effects. Furthermore, using structure analysis, human mutations can also be
precisely mapped onto these structures, providing a basis for how they can
alter transporter function.
More Published Papers
- Dr. Coleman is postdoctoral fellow, OHSU Vollum Institute
- Dr. Gouaux is professor and senior scientist, OHSU Vollum Institute, and adjunct professor of biochemistry and molecular biology, OHSU School of Medicine
Pictured above: Dr. Jonathan Coleman
About the OHSU School of Medicine Paper of the Month
The OHSU School of Medicine spotlights a recently published faculty research paper each month. The goals are to describe to the public the exceptional research happening at OHSU as well as inform our faculty of the innovative work underway across the school’s departments, institutes and disciplines. The monthly paper is selected by Associate Dean for Basic Research Mary Heinricher, Ph.D. Learn more