15 April 2019

4 Researchers From Department of Neuroscience Publish Article in Nature Communications

Anne Kathrine Nielsen, Søren G. F. Rasmussen, Ulrik Gether and Claus Løland publish the article Conformational dynamics of the human serotonin transporter during substrate and drug binding in Nature Communications on 11 April 2019.

The serotonin transporter (SERT), a member of the neurotransmitter:sodium symporter family, is responsible for termination of serotonergic signaling by re-uptake of serotonin (5-HT) into the presynaptic neuron. Its key role in synaptic transmission makes it a major drugtarget, e.g. for the treatment of depression, anxiety and post-traumatic stress. Here, we apply hydrogen-deuterium exchange mass spectrometry to probe the conformational dynamics of human SERT in the absence and presence of known substrates and targeted drugs. Our results reveal significant changes in dynamics in distinct SERT regions upon binding of co-transported ions (Na+/K+). The binding of 5-HT and the drugs S-citalopram, cocaine and ibogaine induces additional conformational changes in other domains of the protein. In all, our results provide a comprehensive direct view of the conformational response of SERT upon binding both biologically relevant substrate/ions and ligands of pharmaceutical interest, thus advancing ourunderstanding of the structure-function relationship in SERT.

Read the full article here.