6D32

Crystal structure of Xenopus Smoothened in complex with cyclopamine

6D32 の概要

• エントリーDOI: 10.2210/pdb6d32/pdb
• 分子名称: Smoothened,Soluble cytochrome b562,Smoothened, Cyclopamine (2 entities in total)
• 機能のキーワード: gpcr, hedgehog signaling, class frizzled, sterol, membrane protein
• 由来する生物種: Xenopus laevis (African clawed frog); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 69807.54

構造登録者

Huang, P.,Zheng, S.,Kim, Y.,Kruse, A.C.,Salic, A. (登録日: 2018-04-14, 公開日: 2018-05-23, 最終更新日: 2023-10-04)

主引用文献

Huang, P.,Zheng, S.,Wierbowski, B.M.,Kim, Y.,Nedelcu, D.,Aravena, L.,Liu, J.,Kruse, A.C.,Salic, A.
Structural Basis of Smoothened Activation in Hedgehog Signaling.
Cell, 174:312-324.e16, 2018

PubMed Abstract: The 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 π-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.

PubMed: 29804838
DOI: 10.1016/j.cell.2018.04.029

実験手法

X-RAY DIFFRACTION (3.751 Å)