The Role of Cholesterol in Activating a Key Cellular Signaling Pathway

(A) Cholesterol (yellow) binds and activates Smoothened (green) via a tunnel to the membrane inner leaflet (outlined in red.) (B) Clinical anticancer drugs block Smoothened by clashing with and displacing the bound cholesterol, suggesting new strategies to design more effective inhibitors.

Hedgehog signaling promotes embryonic development and, when aberrant, can lead to malignancies. The seven-transmembrane transducer Smoothened (SMO) occupies a key node in this pathway and is activated by cholesterol. However, how smoothened binds cholesterol and activates SMO had not been determined. A crystal structure by Myers and colleagues has revealed how cholesterol binds and activates SMO. Remarkably, the cholesterol-binding site resides within a pocket deep inside the seven-transmembrane domain, rather than on a surface location, as proposed previously. This insight suggests new strategies for overcoming clinical resistance to SMO inhibitors.


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Smoothened stimulation by membrane sterols drives Hedgehog pathway activity. Deshpande I, Liang J, Hedeen D, Roberts KJ, Zhang Y, Ha B, Latorraca NR, Faust B, Dror RO, Beachy PA, Myers BR, Manglik A. Nature. 2019 Jul;571(7764):284.

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