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  • Perspective
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Regulation of the oncoprotein Smoothened by small molecules

Nature Chemical Biology volume 11, pages 246–255 (2015)Cite this article

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Abstract

The Hedgehog pathway is critical for animal development and has been implicated in multiple human malignancies. Despite great interest in targeting the pathway pharmacologically, many of the principles underlying the signal transduction cascade remain poorly understood. Hedgehog ligands are recognized by a unique receptor system that features the transporter-like protein Patched and the G protein–coupled receptor (GPCR)-like Smoothened (SMO). The biochemical interaction between these transmembrane proteins is the subject of intensive efforts. Recent structural and functional studies have provided great insight into the small-molecule regulation of SMO through identification of two distinct ligand-binding sites. In this Perspective, we review these recent findings and relate them to potential mechanisms for the endogenous regulation of SMO.

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Figure 1: Overview of the vertebrate Hedgehog signaling pathway.
Figure 2: Small-molecule interactions with the SMO heptahelical bundle.
Figure 3: SMO mutations found in cancer.
Figure 4: Comparison between FZD8 CRD and Smo CRD structures.
Figure 5: Proposed models for the endogenous regulation of vertebrate SMO.

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Acknowledgements

We thank A. Bruce for assistance with the graphical abstract. We apologize to all investigators whose work could not be cited due to reference limitations.

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Authors and Affiliations

  1. Department of Molecular Oncology, Genentech Inc., San Francisco, California, USA

    Hayley J Sharpe & Frederic J de Sauvage

  2. Department of Structural Biology, Genentech Inc., San Francisco, California, USA

    Weiru Wang

  3. Department of Early Discovery Biochemistry, Genentech Inc., San Francisco, California, USA

    Rami N Hannoush

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  1. Hayley J Sharpe
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Correspondence to Rami N Hannoush or Frederic J de Sauvage.

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H.J.S. is employed as a postdoctoral researcher by Genentech Inc. R.N.H., W.W. and F.J.d.S. are employed by Genentech Inc. and own shares in Roche.

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Sharpe, H., Wang, W., Hannoush, R. et al. Regulation of the oncoprotein Smoothened by small molecules. Nat Chem Biol 11, 246–255 (2015). https://doi.org/10.1038/nchembio.1776

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