The coupling mechanism of ligands with SERT distinguishes substrates from inhibitors (raw data)

<p>Raw data of the manuscript:&nbsp;Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors</p> <p><strong>Abstract:</strong></p> <p>The presynaptic serotonin transporter (SERT) reuptakes the serotonin (5HT) released into the synaptic cleft, thus ensuring&nbsp;temporal and spatial regulation of serotonergic signalling.&nbsp;Clinically approved drugs used for the treatment of neurological disorders, including depression and&nbsp;anxiety modulate SERT by trapping the transporter in the outward-open conformation. Illicit drugs of abuse as amphetamines act as substrates but reverse the transport direction, thereby releasing intracellular accumulated 5HT.&nbsp;Both mechanisms increase extracellular 5HT levels.&nbsp;Stoichiometry of the transport cycle has been described by kinetic schemes, the structures of the main conformations within the transport cycle revealed static coordinates. By combining <em>in-silico</em> approaches with <em>in-vitro</em> experiments and making use of a homologous series of 5HT analogues, we decoded&nbsp;the essential coupling mechanism between the substrate and the transporter which triggers uptake. The free energy calculations showed that only scaffold-bound substrates can correctly close the extracellular gate by pulling on the bundle domain through long-range electrostatic interactions. The associated spatial and physico-chemical requirements define substrate and inhibitor properties, opening new possibilities for rational drug design approaches.</p>