Journal
NATURE
Volume 535, Issue 7613, Pages 517-522Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature18934
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Funding
- Cancer Research UK [C20724/A14414]
- US National Institutes of Health [GM106078, HL067773]
- Wellcome Trust [102890/Z/13/Z, 092970/Z/10/Z, 090532/Z/09/Z]
- Taylor Family Institute for Psychiatric Research
- NDM Oxford
- Medical Research Council UK
- National Science Foundation
- Wellcome Trust [092970/Z/10/Z] Funding Source: Wellcome Trust
- Cancer Research UK [14414] Funding Source: researchfish
- Medical Research Council [1514534] Funding Source: researchfish
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Developmental signals of the Hedgehog (Hh) and Wnt families are transduced across the membrane by Frizzled-class G-protein-coupled receptors (GPCRs) composed of both a heptahelical transmembrane domain (TMD) and an extracellular cysteine-rich domain (CRD). How the large extracellular domains of GPCRs regulate signalling by the TMD is unknown. We present crystal structures of the Hh signal transducer and oncoprotein Smoothened, a GPCR that contains two distinct ligand-binding sites: one in its TMD and one in the CRD. The CRD is stacked atop the TMD, separated by an intervening wedge-like linker domain. Structure-guided mutations show that the interface between the CRD, linker domain and TMD stabilizes the inactive state of Smoothened. Unexpectedly, we find a cholesterol molecule bound to Smoothened in the CRD binding site. Mutations predicted to prevent cholesterol binding impair the ability of Smoothened to transmit native Hh signals. Binding of a clinically used antagonist, vismodegib, to the TMD induces a conformational change that is propagated to the CRD, resulting in loss of cholesterol from the CRD-linker domain-TMD interface. Our results clarify the structural mechanism by which the activity of a GPCR is controlled by ligand-regulated interactions between its extracellular and transmembrane domains.
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