Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/103764
Title: Structure and function of the smoothened extracellular domain in vertebrate hedgehog signaling
Authors: Rohatgi, Rajat
Nachtergaele, Sigrid
Whalen, Daniel M
Mydock, Laurel K
Zhao, Zhonghua
Malinauskas, Tomas
Krishnan, Kathiresan
Covey, Douglas F
Siebold, Christian
Ingham, Philip William
Keywords: DRNTU::Science::Medicine
Issue Date: 2013
Source: Nachtergaele, S., Whalen, D. M., Mydock, L. K., Zhao, Z., Malinauskas, T., Krishnan, K., Ingham, P. W., Covey, D. F., Siebold, C., & Rohatgi, R. (2013). Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling. eLife, 2(0), e01340-e01340.
Series/Report no.: eLife
Abstract: The Hedgehog (Hh) signal is transduced across the membrane by the heptahelical protein Smoothened (Smo), a developmental regulator, oncoprotein and drug target in oncology. We present the 2.3 Å crystal structure of the extracellular cysteine rich domain (CRD) of vertebrate Smo and show that it binds to oxysterols, endogenous lipids that activate Hh signaling. The oxysterol-binding groove in the Smo CRD is analogous to that used by Frizzled 8 to bind to the palmitoleyl group of Wnt ligands and to similar pockets used by other Frizzled-like CRDs to bind hydrophobic ligands. The CRD is required for signaling in response to native Hh ligands, showing that it is an important regulatory module for Smo activation. Indeed, targeting of the Smo CRD by oxysterol-inspired small molecules can block signaling by all known classes of Hh activators and by clinically relevant Smo mutants.
URI: https://hdl.handle.net/10356/103764
http://hdl.handle.net/10220/19293
ISSN: 2050-084X
DOI: http://dx.doi.org/10.7554/eLife.01340.001
Rights: © 2013 Nachtergaele et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles

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