Influence of Cholesterol and its Stereoisomers on Members of the Serotonin Receptor Family

Victoria Oakes, Carmen Domene

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Despite the ubiquity of cholesterol within the cell membrane, the mechanism by which it influences embedded proteins remains elusive. Numerous G-protein coupled receptors exhibit dramatic responses to membrane cholesterol with regard to the ligand-binding affinity and functional properties, including the 5-HT receptor family. Here, we use over 25 μs of unbiased atomistic molecular dynamics simulations to identify cholesterol interaction sites in the 5-HT 1B and 5-HT 2B receptors and evaluate their impact on receptor structure. Susceptibility to membrane cholesterol is shown to be subtype dependent and determined by the quality of interactions between the extracellular loops. Charged residues are essential for maintaining the arrangement of the extracellular surface in 5-HT 2B ; in the absence of such interactions, the extracellular surface of the 5-HT 1B is malleable, populating a number of distinct conformations. Elevated cholesterol density near transmembrane helix 4 is considered to be conducive to the conformation of extracellular loop 2. Occupation of this site is also shown to be stereospecific, illustrated by differential behavior of nat-cholesterol isomers, ent- and epi-cholesterol. In simulations containing the endogenous agonist, serotonin, cholesterol binding at transmembrane helix 4 biases bound serotonin molecules toward an unexpected binding mode in the extended binding pocket. The results highlight the capability of membrane cholesterol to influence the mobility of the extracellular surface in the 5-HT 1 receptor family and manipulate the architecture of the extracellular ligand-binding pocket.

Original languageEnglish
Pages (from-to)1633-1649
Number of pages17
JournalJournal of Molecular Biology
Issue number8
Early online date8 Mar 2019
Publication statusPublished - 5 Apr 2019

Bibliographical note

Copyright © 2019 Elsevier Ltd. All rights reserved.


  • GPCRs
  • membrane proteins
  • molecular dynamics simulations
  • protein–lipid interactions
  • stereospecificity

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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