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PDBsum entry 4c7a
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Signaling protein
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PDB id
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4c7a
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PDB id:
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| Name: |
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Signaling protein
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Title:
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Crystal structure of the smoothened crd, selenomethionine-labeled
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Structure:
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Smoothened. Chain: a, b. Fragment: cysteine-rich domain (crd), residues 28-210. Engineered: yes
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Source:
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Danio rerio. Zebrafish. Organism_taxid: 7955. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_variant: rosetta plyss.
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Resolution:
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2.30Å
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R-factor:
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0.238
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R-free:
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0.284
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Authors:
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S.Nachtergaele,D.M.Whalen,L.K.Mydock,Z.Zhao,T.Malinauskas,K.Krishnan, P.W.Ingham,D.F.Covey,R.Rohatgi,C.Siebold
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Key ref:
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S.Nachtergaele
et al.
(2013).
Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling.
Elife,
2,
e01340.
PubMed id:
DOI:
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Date:
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20-Sep-13
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Release date:
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06-Nov-13
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PROCHECK
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Headers
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References
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Q5RH73
(Q5RH73_DANRE) -
Protein smoothened from Danio rerio
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Seq:
Struc:
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822 a.a.
117 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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DOI no:
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Elife
2:e01340
(2013)
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PubMed id:
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Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling.
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S.Nachtergaele,
D.M.Whalen,
L.K.Mydock,
Z.Zhao,
T.Malinauskas,
K.Krishnan,
P.W.Ingham,
D.F.Covey,
C.Siebold,
R.Rohatgi.
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ABSTRACT
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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.
DOI:http://dx.doi.org/10.7554/eLife.01340.001.
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Links
