Structural basis for recognition of diverse antidepressants by the human serotonin transporter

Selective serotonin reuptake inhibitors are clinically prescribed antidepressants that act by increasing the local concentrations of neurotransmitters at synapses and in extracellular spaces via blockade of the serotonin transporter. Here we report X-ray structures of engineered thermostable variants of the human serotonin transporter bound to the antidepressants sertraline, fluvoxamine, and paroxetine. The drugs prevent serotonin binding by occupying the central substrate-binding site and stabilizing the transporter in an outward-open conformation. These structures explain how residues within the central site orchestrate binding of chemically diverse inhibitors and mediate transporter drug selectivity. The X-ray structures of engineered variants of the human serotonin transporter show that the antidepressants sertraline, fluvoxamine and paroxetine occupy the central substrate-binding site and stabilize the transporter in an outward-open conformation.

• Publication year

  2017

• Venue

  Nature Structural & Molecular Biology

• Publication date

  2017-10-17

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1038/s41594-018-0026-8PMID 29379174PMCID PMC5962350
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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