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PDBsum entry 6d32
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Membrane protein
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PDB id
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6d32
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References listed in PDB file
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Key reference
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Title
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Structural basis of smoothened activation in hedgehog signaling.
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Authors
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P.Huang,
S.Zheng,
B.M.Wierbowski,
Y.Kim,
D.Nedelcu,
L.Aravena,
J.Liu,
A.C.Kruse,
A.Salic.
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Ref.
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Cell, 2018,
174,
312.
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PubMed id
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Abstract
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The seven-transmembrane-spanning protein Smoothened is the central transducer in
Hedgehog signaling, a pathway fundamental in development and in cancer.
Smoothened is activated by cholesterol binding to its extracellular
cysteine-rich domain (CRD). How this interaction leads to changes in the
transmembrane domain and Smoothened activation is unknown. Here, we report
crystal structures of sterol-activated Smoothened. The CRD undergoes a dramatic
reorientation, allosterically causing the transmembrane domain to adopt a
conformation similar to active G-protein-coupled receptors. We show that
Smoothened contains a unique inhibitory π-cation lock, which is broken on
activation and is disrupted in constitutively active oncogenic mutants.
Smoothened activation opens a hydrophobic tunnel, suggesting a pathway for
cholesterol movement from the inner membrane leaflet to the CRD. All Smoothened
antagonists bind the transmembrane domain and block tunnel opening, but
cyclopamine also binds the CRD, inducing the active transmembrane conformation.
Together, these results define the mechanisms of Smoothened activation and
inhibition.
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