title: Cholesterol-β1 AR interaction versus cholesterol-β2 AR interaction.
abstract: Two 8-µs all-atom molecular dynamics simulations have been performed on the two highly homologous G protein-coupled receptor (GPCR) subtypes, β1 - and β2 -adrenergic receptors, which were embedded in a lipid bilayer with randomly dispersed cholesterol molecules. During the simulations, cholesterol molecules accumulate to different surface regions of the two receptors, suggesting the subtype specificity of cholesterol-β-adrenergic receptor interaction and providing some clues to the physiological difference of the two subtypes. Meanwhile, comparison between the two receptors in interacting with cholesterols shed some new light on general determinants of cholesterol binding to GPCRs. Our results indicate that although the concave surface, charged residues and aromatic residues are important, neither of these stabilizing factors is indispensable for a cholesterol interaction site. Different combinations of these factors lead to the diversified binding modes of cholesterol binding to the receptors. Our long-time simulations, for the first time, revealed the pathway of a cholesterol molecule entering the consensus cholesterol motif (CCM) site, and the binding process of cholesterol to CCM is accompanied by a side chain flipping of the conserved Trp4.50. Moreover, the simulation results suggest that the I-/V-/L-rich region on the extracellular parts of helix 6 might be an alternatively conserved cholesterol-binding site for the class-A GPCRs.
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Institute of Genetics, College of Life Science, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Cang
authors.forename: Linlin
authors.initials: L
authors.lastname: Yang
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zheng
authors.forename: Kunqian
authors.initials: K
authors.lastname: Yu
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Yang
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism*; D016384:Consensus Sequence; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D018342:Receptors, Adrenergic, beta-1 / Q000737:chemistry / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000378:metabolism*; D014421:Turkey
chemical_list: D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D002784:Cholesterol
keywords: G protein-coupled receptor; cholesterol-binding site; molecular dynamics simulation; β-adrenergic receptor