caa a22 4500 528785591 20191104030335.0 cr unu---uuuuu 180924e20161129xx s 000 0 eng 10.3929/ethz-b-000123638 doi 10.7554/eLife.18432 doi (ETHRESEARCH)oai:www.research-collection.ethz.ch:20.500.11850/123638 Mechanism of allosteric regulation of β2-adrenergic receptor by cholesterol [Elektronische Daten] [Moutusi Manna, Miia Niemelä, Joona Tynkkynen, Matti Javanainen, Waldemar Kulig, Daniel J.; id_orcid 0000-0003-3075-0665 Müller, Tomasz Rog, Ilpo Vattulainen] Open access ethresearch 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 β2-adrenergic receptor (β2AR) - a prototypical G protein-coupled receptor - is modulated by cholesterol in an allosteric fashion. Extensive atomistic simulations show that cholesterol regulates β2AR 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 β2AR 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 β2AR, however cholesterol generates the strongest effect. The results highlight the capacity of lipids to regulate the conformation of membrane receptors through specific interactions. Creative Commons Attribution 4.0 International http://creativecommons.org/licenses/by/4.0 ethresearch Manna Moutusi joint author Niemelä Miia joint author Tynkkynen Joona joint author Javanainen Matti joint author Kulig Waldemar joint author Müller Daniel J.; id_orcid 0000-0003-3075-0665 joint author Rog Tomasz joint author Vattulainen Ilpo joint author eLife Cambridge : eLife Sciences Publications 5, p. e18432 http://hdl.handle.net/20.500.11850/123638 text/html WWW-Backlink auf das Repository (Open access) 1 Journal Article ethresearch ETHRESEARCH 856 40 http://hdl.handle.net/20.500.11850/123638 text/html WWW-Backlink auf das Repository (Open access) ETHRESEARCH 700 1- Manna Moutusi joint author ETHRESEARCH 700 1- Niemelä Miia joint author ETHRESEARCH 700 1- Tynkkynen Joona joint author ETHRESEARCH 700 1- Javanainen Matti joint author ETHRESEARCH 700 1- Kulig Waldemar joint author ETHRESEARCH 700 1- Müller Daniel J.; id_orcid 0000-0003-3075-0665 joint author ETHRESEARCH 700 1- Rog Tomasz joint author ETHRESEARCH 700 1- Vattulainen Ilpo joint author ETHRESEARCH 773 0- eLife Cambridge : eLife Sciences Publications 5, p. e18432 BK010053 XK010053 XK010000 ETHRESEARCH ETHRESEARCH ETHRESEARCH Journal Article Open access