Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors

Ralph Gradisch, Katharina Schlögl, Erika Lazzarin, Marco Niello, Julian Maier, Felix P. Mayer, Leticia Alves da Silva, Sophie M. C. Skopec, Randy D. Blakely, Harald H. Sitte, Marko D. Mihovilovic and Thomas Stockner ()
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Ralph Gradisch: Medical University of Vienna, Institute of Physiology and Pharmacology
Katharina Schlögl: TU Wien, Institute of Applied Synthetic Chemistry
Erika Lazzarin: Medical University of Vienna, Institute of Physiology and Pharmacology
Marco Niello: Medical University of Vienna, Institute of Physiology and Pharmacology
Julian Maier: Medical University of Vienna, Institute of Physiology and Pharmacology
Felix P. Mayer: Florida Atlantic University, Department of Biomedical Science
Leticia Alves da Silva: Medical University of Vienna, Institute of Physiology and Pharmacology
Sophie M. C. Skopec: Medical University of Vienna, Institute of Physiology and Pharmacology
Randy D. Blakely: Florida Atlantic University, Department of Biomedical Science
Harald H. Sitte: Medical University of Vienna, Institute of Physiology and Pharmacology
Marko D. Mihovilovic: TU Wien, Institute of Applied Synthetic Chemistry
Thomas Stockner: Medical University of Vienna, Institute of Physiology and Pharmacology

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-023-44637-6

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