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Mapping Cholesterol Interaction Sites on Serotonin Transporter through Coarse-Grained Molecular Dynamics

Author

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  • Mariarosaria Ferraro
  • Matteo Masetti
  • Maurizio Recanatini
  • Andrea Cavalli
  • Giovanni Bottegoni

Abstract

Serotonin transporter (SERT) modulates serotonergic signaling via re-uptake of serotonin in pre-synaptic cells. The inclusion in cholesterol-enriched membrane domains is crucial for SERT activity, suggesting a cross-talk between the protein and the sterol. Here, we develop a protocol to identify potential cholesterol interaction sites coupling statistical analysis to multi-microsecond coarse-grained molecular dynamics simulations of SERT in a previously validated raft-like membrane model. Six putative sites were found, including a putative CRAC motif on TM4 and a CARC motif on TM10. Among them, four hot-spots near regions related to ion binding, transport, and inhibition were detected. Our results encourage prospective studies to unravel mechanistic features of the transporter and related drug discovery implications.

Suggested Citation

  • Mariarosaria Ferraro & Matteo Masetti & Maurizio Recanatini & Andrea Cavalli & Giovanni Bottegoni, 2016. "Mapping Cholesterol Interaction Sites on Serotonin Transporter through Coarse-Grained Molecular Dynamics," PLOS ONE, Public Library of Science, vol. 11(12), pages 1-24, December.
    • Handle: RePEc:plo:pone00:0166196
    DOI: 10.1371/journal.pone.0166196
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