Mechanism of allosteric regulation of β2-adrenergic receptor by cholesterol

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Manna , M , Niemelä , M , Tynkkynen , J , Javanainen , M , Kulig , W , Müller , D J , Rog , T & Vattulainen , I 2016 , ' Mechanism of allosteric regulation of β2-adrenergic receptor by cholesterol ' eLife , vol. 5 , e18432 . DOI: 10.7554/eLife.18432

Title: Mechanism of allosteric regulation of β2-adrenergic receptor by cholesterol
Author: Manna, Moutusi; Niemelä, Miia; Tynkkynen, Joona; Javanainen, Matti; Kulig, Waldemar; Müller, Daniel J.; Rog, Tomasz; Vattulainen, Ilpo
Contributor: University of Helsinki, Materials Physics
University of Helsinki, Department of Physics
University of Helsinki, Department of Physics
Date: 2016
Language: eng
Number of pages: 21
Belongs to series: eLife
ISSN: 2050-084X
URI: http://hdl.handle.net/10138/174799
Abstract: There is evidence that lipids can be allosteric regulators of membrane protein structure and activation. However, there are no data showing how exactly the regulation emerges from specific lipid-protein interactions. Here we show in atomistic detail how the human b2- adrenergic receptor (b2AR) – a prototypical G protein-coupled receptor – is modulated by cholesterol in an allosteric fashion. Extensive atomistic simulations show that cholesterol regulates b2AR by limiting its conformational variability. The mechanism of action is based on the binding of cholesterol at specific high-affinity sites located near the transmembrane helices 5–7 of the receptor. The alternative mechanism, where the b2AR conformation would be modulated by membrane-mediated interactions, plays only a minor role. Cholesterol analogues also bind to cholesterol binding sites and impede the structural flexibility of b2AR, however cholesterol generates the strongest effect. The results highlight the capacity of lipids to regulate the conformation of membrane receptors through specific interactions.
Subject: 114 Physical sciences
Biological Physics
Biophysics
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