5KZV

Crystal structure of the xenopus Smoothened cysteine-rich domain (CRD) in complex with 20(S)-hydroxycholesterol

5KZV の概要

• エントリーDOI: 10.2210/pdb5kzv/pdb
• 分子名称: Smoothened, (3alpha,8alpha)-cholest-5-ene-3,20-diol (3 entities in total)
• 機能のキーワード: hedgehog signaling, gpcr, cysteine-rich domain, sterol, signaling protein
• 由来する生物種: Xenopus laevis (African clawed frog)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 14393.71

構造登録者

Huang, P.,Kim, Y.,Salic, A. (登録日: 2016-07-25, 公開日: 2016-08-17, 最終更新日: 2023-10-04)

主引用文献

Huang, P.,Nedelcu, D.,Watanabe, M.,Jao, C.,Kim, Y.,Liu, J.,Salic, A.
Cellular Cholesterol Directly Activates Smoothened in Hedgehog Signaling.
Cell, 166:1176-1187.e14, 2016

PubMed Abstract: In vertebrates, sterols are necessary for Hedgehog signaling, a pathway critical in embryogenesis and cancer. Sterols activate the membrane protein Smoothened by binding its extracellular, cysteine-rich domain (CRD). Major unanswered questions concern the nature of the endogenous, activating sterol and the mechanism by which it regulates Smoothened. We report crystal structures of CRD complexed with sterols and alone, revealing that sterols induce a dramatic conformational change of the binding site, which is sufficient for Smoothened activation and is unique among CRD-containing receptors. We demonstrate that Hedgehog signaling requires sterol binding to Smoothened and define key residues for sterol recognition and activity. We also show that cholesterol itself binds and activates Smoothened. Furthermore, the effect of oxysterols is abolished in Smoothened mutants that retain activation by cholesterol and Hedgehog. We propose that the endogenous Smoothened activator is cholesterol, not oxysterols, and that vertebrate Hedgehog signaling controls Smoothened by regulating its access to cholesterol.

PubMed: 27545348
DOI: 10.1016/j.cell.2016.08.003

実験手法

X-RAY DIFFRACTION (1.616 Å)