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Crystal structure of Xenopus Smoothened in complex with cholesterolCrystal structure of Xenopus Smoothened in complex with cholesterol
Structural highlights
FunctionC562_ECOLX Electron-transport protein of unknown function. Publication Abstract from PubMedThe seven-transmembrane-spanning protein Smoothened is the central transducer in Hedgehog signaling, a pathway fundamental in development and in cancer. Smoothened is activated by cholesterol binding to its extracellular cysteine-rich domain (CRD). How this interaction leads to changes in the transmembrane domain and Smoothened activation is unknown. Here, we report crystal structures of sterol-activated Smoothened. The CRD undergoes a dramatic reorientation, allosterically causing the transmembrane domain to adopt a conformation similar to active G-protein-coupled receptors. We show that Smoothened contains a unique inhibitory pi-cation lock, which is broken on activation and is disrupted in constitutively active oncogenic mutants. Smoothened activation opens a hydrophobic tunnel, suggesting a pathway for cholesterol movement from the inner membrane leaflet to the CRD. All Smoothened antagonists bind the transmembrane domain and block tunnel opening, but cyclopamine also binds the CRD, inducing the active transmembrane conformation. Together, these results define the mechanisms of Smoothened activation and inhibition. Structural Basis of Smoothened Activation in Hedgehog Signaling.,Huang P, Zheng S, Wierbowski BM, Kim Y, Nedelcu D, Aravena L, Liu J, Kruse AC, Salic A Cell. 2018 May 15. pii: S0092-8674(18)30522-1. doi: 10.1016/j.cell.2018.04.029. PMID:29804838[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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