Title : X-ray structures and mechanism of the human
serotonin transporter
Abstract :
- The serotonin transporter ( SERT ) terminates serotonergic signalling through the sodium- and chloride-dependent reuptake of neurotransmitter into presynaptic neurons
- SERT is a target for antidepressant and psychostimulant drugs, which block reuptake and prolong neurotransmitter signalling
- Here we report X-ray crystallographic structures of human SERT at 3 .15 Å resolution bound to the antidepressants (S)-citalopram or paroxetine
- Antidepressants lock SERT in an outward-open conformation by lodging in the central binding site , located between transmembrane helices 1 , 3, 6, 8 and 10, directly blocking serotonin binding
- We further identify the location of an allosteric site in the complex as residing at the periphery of the extracellular vestibule, interposed between extracellular loops 4 and 6 and transmembrane helices 1 , 6, 10 and 11
- Occupancy of the allosteric site sterically hinders ligand unbinding from the central site , providing an explanation for the action of (S)-citalopram as an allosteric ligand
- These structures define the mechanism of antidepressant action in SERT , and provide blueprints for future drug design
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