title: G protein coupled receptor interactions with cholesterol deep in the membrane.
abstract: G protein coupled receptors (GPCRs) are located in membranes rich in cholesterol. The membrane spanning surfaces of GPCRs contain exposed backbone carbonyl groups and residue side chains potentially capable of forming hydrogen bonds to cholesterol molecules buried deep within the hydrophobic core of the lipid bilayer. Coarse-grained molecular dynamics (CGMD) simulations allow the observation of GPCRs in cholesterol-containing lipid bilayers for long times (50μs), sufficient to ensure equilibration of the system. We have detected a number of deep cholesterol binding sites on β2adrenergic and A2Aadenosine receptors, and shown changes in these sites on agonist binding. The requirements for binding are modest, just a potential hydrogen bond partner close to a cleft or hole in the surface. This makes it likely that similar binding sites for cholesterol will exist on other classes of membrane protein.
authors.affiliation: School of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom.
authors.forename: Samuel
authors.initials: S
authors.lastname: Genheden
authors.affiliation: School of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom; Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Essex
authors.affiliation: Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom; Centre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom. Electronic address: agl@soton.ac.uk.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Lee
mesh_terms: D001665:Binding Sites; D002784:Cholesterol / Q000737:chemistry* / Q000378:metabolism*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D008566:Membranes / Q000737:chemistry* / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D011485:Protein Binding / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D008051:Lipid Bilayers; D008565:Membrane Proteins; D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled; D002784:Cholesterol
keywords: Binding sites; Cholesterol; G protein coupled receptor; GPCR; Lipids; Molecular dynamics