Conformational dynamics of the human serotonin transporter during substrate and drug binding.
Nature communications – April 11, 2019
Source: PubMed
Summary
The brain's serotonin transporter, a key target for antidepressants, dynamically shifts its shape to regulate mood. Using advanced mass spectrometry, scientists observed how this vital protein changes form when interacting with serotonin, essential ions, and various drugs like citalopram or cocaine. These direct observations reveal specific structural responses, significantly advancing our understanding of how this transporter works. This insight is crucial for developing better treatments for depression and anxiety.
Abstract
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 drug target, 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 regions TM1, EL3, EL4, and TM12 upon binding co-transported ions (Na+/K+) and ligand-mediated changes in TM1, EL3 and EL4 upon binding 5-HT, the drugs S-citalopram, cocaine and ibogaine. 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 our understanding of the structure-function relationship in SERT.