Substrate-triggered occlusion in the human serotonin transporter unveiled a new and fully occluded structure

The serotonin transporter (SERT; SLC6A4) is an important pre-synaptic protein involved in sodium-dependent re-uptake of serotonin (5HT), shaping the concentration of 5HT available for the post-synaptic receptor binding. Inadequate handling of synaptic monoamine levels have been associated with neuropsychiatric diseases like major depression disorder, affecting over 260 million people world-wide. SERT has therefore been implicated as an upmost important pharmacological target. High-resolution structures of SLC6 members including SERT confirmed its conserved 12 transmembrane helical architecture and the presence of the orthosteric binding site (S1) halfway through the membrane.