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Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling

DOI: 10.7554/eLife.01340 DOI Help
PMID: 24171105 PMID Help

Authors: Sigrid Nachtergaele (Stanford University School of Medicine) , Daniel Whalen (University of Oxford) , Laurel K Mydock (Washington University School of Medicine) , Zhonghua Zhao (A*STAR Institute of Molecular and Cell Biology) , Tomas Malinauskas (University of Oxford) , Kathiresan Krishnan (Washington University School of Medicine) , Philip W Ingham (A*STAR Institute of Molecular and Cell Biology) , Douglas F Covey (Washington University School of Medicine) , Christian Siebold (Wellcome Trust Centre for Human Genetics, University of Oxford) , Rajat Rohatgi (Stanford University School of Medicine)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Elife , VOL 2

State: Published (Approved)
Published: October 2013

Open Access Open Access

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

Subject Areas: Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography

Other Facilities: ESRF