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

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ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS HEDGEHOG-INTERACTING PROTEIN IS A

MULTIMODAL ANTAGONIST OF HEDGEHOG SIGNALLING Article Open access 09 December 2021 STEROLS IN AN INTRAMOLECULAR CHANNEL OF SMOOTHENED MEDIATE HEDGEHOG SIGNALING Article 14 September 2020 A

PKA INHIBITOR MOTIF WITHIN SMOOTHENED CONTROLS HEDGEHOG SIGNAL TRANSDUCTION Article 06 October 2022 ACCESSION CODES ACCESSIONS PROTEIN DATA BANK * 4C7A * 4F0A * 4JKV * 4N4W * 4O9R * 4QIN

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references 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. AUTHOR

INFORMATION AUTHORS AND AFFILIATIONS * Department of Molecular Oncology, Genentech Inc., San Francisco, California, USA Hayley J Sharpe & Frederic J de Sauvage * Department of

Structural Biology, Genentech Inc., San Francisco, California, USA Weiru Wang * Department of Early Discovery Biochemistry, Genentech Inc., San Francisco, California, USA Rami N Hannoush

Authors * Hayley J Sharpe View author publications You can also search for this author inPubMed Google Scholar * Weiru Wang View author publications You can also search for this author

inPubMed Google Scholar * Rami N Hannoush View author publications You can also search for this author inPubMed Google Scholar * Frederic J de Sauvage View author publications You can also

search for this author inPubMed Google Scholar CORRESPONDING AUTHORS Correspondence to Rami N Hannoush or Frederic J de Sauvage. ETHICS DECLARATIONS COMPETING INTERESTS 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. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS

ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 24 October 2014 * Accepted: 19 February 2015 * Published: 18 March 2015 * Issue Date: April 2015 * DOI:

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