Abstract
SummaryTransduction 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.
Highlights
The Smoothened (SMO) receptor is a critical component of the (Hh) signaling cascade, which controls a variety of key developmental processes, including human embryonic tissue patterning and regulation of adult stem cells (Briscoe and Therond, 2013)
SMO is a member of the Frizzled class of G-protein-coupled receptors (GPCRs) and is found at the plasma membrane
Its structural architecture consists of an extracellular cysteine-rich domain (CRD), stacked on top of a short linker domain (LD), and a hepta-helical transmembrane domain (7TMD) (Byrne et al, 2016; Zhang et al, 2017) (Figure 1)
Summary
The Smoothened (SMO) receptor is a critical component of the (Hh) signaling cascade, which controls a variety of key developmental processes, including human embryonic tissue patterning and regulation of adult stem cells (Briscoe and Therond, 2013). Aberrant activation of SMO causes uncontrolled Hh signaling and a variety of cancers (Wu et al, 2017). As such SMO is of major academic and pharmaceutical interest, and is the target of two FDA-approved drugs for treating basal cell carcinomas, vismodegib (Dlugosz et al, 2012) and sonidegib (Burness, 2015). SMO is a member of the Frizzled class of G-protein-coupled receptors (GPCRs) and is found at the plasma membrane. 11 crystal structures containing the SMO 7TMD have been solved (Byrne et al, 2018), revealing structural similarity to the presumed inactive state of class A GPCRs (Wang et al, 2013). SMO exhibits
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