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

Jonathan A. Coleman, Eric Gouaux

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)170-175
Number of pages6
JournalNature Structural and Molecular Biology
Volume25
Issue number2
DOIs
StatePublished - Feb 1 2018

Fingerprint

Serotonin Plasma Membrane Transport Proteins
Antidepressive Agents
Binding Sites
Serotonin Agents
Fluvoxamine
Sertraline
Paroxetine
Serotonin Uptake Inhibitors
Extracellular Space
Synapses
Neurotransmitter Agents
X-Rays
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Structural basis for recognition of diverse antidepressants by the human serotonin transporter. / Coleman, Jonathan A.; Gouaux, Eric.

In: Nature Structural and Molecular Biology, Vol. 25, No. 2, 01.02.2018, p. 170-175.

Research output: Contribution to journalArticle

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