Serotonin transporter structure revealed

NIH | APRIL 20, 2016

A research team set out to solve the structure of the human serotonin transporter and determine how selective serotonin reuptake inhibitors (SSRIs) interact with it.

Slice through the human serotonin transporter structure illustrating the SSRI binding sites. Citalopram is shown at the central site in purple and at the allosteric site in yellow. Image credit: Jonathan A. Coleman, Evan M. Green, and Eric Gouaux, Oregon Health and Science University

The serotonin transporter can be difficult to prepare for X-ray crystallography, a technique that creates an image of a protein’s 3-D structure. The protein is normally unstable during the purification and crystallization processes.

The researchers genetically altered the transporter to withstand the temperatures used for isolation. They also added small antibody fragments to the protein solution to encourage crystallization. Using these modifications, they were able to create small crystals suitable for X-ray crystallography.

The technique yielded a detailed molecular map of the human serotonin transporter’s structure. The scientists were able to identify where different molecules interact with the transporter, including the sodium and chloride ions that are necessary for pumping serotonin.

The group next determined where 2 SSRIs, citalopram (CeleXA) and paroxetine (Paxil), take hold of the transporter. They found that both bind to the pump’s primary central binding site, preventing serotonin from binding and being pumped into the neuron.

The SSRIs also fit in a second site on the protein, called an “allosteric” site, which affects how quickly molecules can get out of the central pocket. Thus, compounds that bind to this allosteric site can affect transport activity as well.

The researchers could also see where genetic variations associated with various psychiatric disorders are located in the transporter. Knowing the structure of the transporter can help researchers gain insights into the molecular causes of these disorders and of antidepressant treatment resistance.

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