Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Transduction of Hedgehog signals across the plasma membrane is facilitated by the class F G-protein-coupled-receptor (GPCR) Smoothened (SMO). Recent studies suggest that SMO is modulated via interactions of its transmembrane (TM) domain with cholesterol. We apply molecular dynamics simulations of SMO embedded in cholesterol containing lipid bilayers, revealing a direct interaction of cholesterol with the TM domain at regions distinct from those observed in class A GPCRs. In particular the extracellular tips of helices TM2 and TM3 form a well-defined cholesterol interaction site. Potential of mean force calculations yield a free energy landscape for cholesterol binding. Alongside analysis of equilibrium cholesterol occupancy, this reveals the existence of a dynamic "greasy patch" interaction with the TM domain of SMO, which may be compared with previously identified lipid interaction sites on other membrane proteins. These predictions provide molecular-level insights into cholesterol interactions with a class F GPCR, suggesting potential druggable sites.

Original publication

DOI

10.1016/j.str.2018.11.003

Type

Journal article

Journal

Structure (London, England : 1993)

Publication Date

03/2019

Volume

27

Pages

549 - 559.e2

Addresses

Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.

Keywords

Humans, Cholesterol, Lipid Bilayers, Phosphatidylinositol 4,5-Diphosphate, Binding Sites, Protein Structure, Secondary, Protein Binding, Models, Molecular, Molecular Dynamics Simulation, Smoothened Receptor, Protein Domains