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Nat Commun. 2019 Apr 11;10(1):1687. doi: 10.1038/s41467-019-09675-z.

Conformational dynamics of the human serotonin transporter during substrate and drug binding.

Author information

1
Protein Analysis Group, Department of Pharmacy, University of Copenhagen, Copenhagen, 2100, Denmark.
2
Laboratory for Membrane Protein Dynamics, Department of Neuroscience, University of Copenhagen, Copenhagen, 2200, Denmark.
3
Department of Neuroscience, University of Copenhagen, Copenhagen, 2200, Denmark.
4
Laboratory for Membrane Protein Dynamics, Department of Neuroscience, University of Copenhagen, Copenhagen, 2200, Denmark. cllo@sund.ku.dk.
5
Protein Analysis Group, Department of Pharmacy, University of Copenhagen, Copenhagen, 2100, Denmark. kasper.rand@sund.ku.dk.

Abstract

The serotonin transporter (SERT), a member of the neurotransmitter:sodium symporter family, is responsible for termination of serotonergic signaling by re-uptake of serotonin (5-HT) into the presynaptic neuron. Its key role in synaptic transmission makes it a major drug target, e.g. for the treatment of depression, anxiety and post-traumatic stress. Here, we apply hydrogen-deuterium exchange mass spectrometry to probe the conformational dynamics of human SERT in the absence and presence of known substrates and targeted drugs. Our results reveal significant changes in dynamics in regions TM1, EL3, EL4, and TM12 upon binding co-transported ions (Na+/K+) and ligand-mediated changes in TM1, EL3 and EL4 upon binding 5-HT, the drugs S-citalopram, cocaine and ibogaine. Our results provide a comprehensive direct view of the conformational response of SERT upon binding both biologically relevant substrate/ions and ligands of pharmaceutical interest, thus advancing our understanding of the structure-function relationship in SERT.

PMID:
30976000
PMCID:
PMC6459873
DOI:
10.1038/s41467-019-09675-z
[Indexed for MEDLINE]
Free PMC Article

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