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Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors
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Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors
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Journal Article
Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors
2024
Overview
The presynaptic serotonin transporter (SERT) clears extracellular serotonin following vesicular release to ensure temporal and spatial regulation of serotonergic signalling and neurotransmitter homeostasis. Prescription drugs used to treat neurobehavioral disorders, including depression, anxiety, and obsessive-compulsive disorder, trap SERT by blocking the transport cycle. In contrast, illicit drugs of abuse like amphetamines reverse SERT directionality, causing serotonin efflux. Both processes result in increased extracellular serotonin levels. By combining molecular dynamics simulations with biochemical experiments and using a homologous series of serotonin analogues, we uncovered the coupling mechanism between the substrate and the transporter, which triggers the uptake of serotonin. Free energy analysis showed that only scaffold-bound substrates could initiate SERT occlusion through attractive long-range electrostatic interactions acting on the bundle domain. The associated spatial requirements define substrate and inhibitor properties, enabling additional possibilities for rational drug design approaches.
The serotonin transporter, targeted by several medications, terminates neurotransmission by clearing serotonin from the synaptic cleft. Combining biochemical results with in silico data, the authors show the key interactions that initiate substrate transport.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/31
/ 14/35
/ 631/114
/ 64/60
/ 9/74
/ 96/109
/ Anxiety
/ Drugs
/ Efflux
/ Humanities and Social Sciences
/ Humans
/ Ligands
/ Obsessive compulsive disorder
/ Science
