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PDBsum entry 6xbl
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Membrane protein
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PDB id
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6xbl
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Contents |
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468 a.a.
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215 a.a.
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336 a.a.
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53 a.a.
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232 a.a.
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References listed in PDB file
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Key reference
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Title
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Sterols in an intramolecular channel of smoothened mediate hedgehog signaling.
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Authors
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X.Qi,
L.Friedberg,
R.De bose-Boyd,
T.Long,
X.Li.
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Ref.
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Nat Chem Biol, 2020,
16,
1368-1375.
[DOI no: ]
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PubMed id
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Abstract
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Smoothened (SMO), a class Frizzled G protein-coupled receptor (class F GPCR),
transduces the Hedgehog signal across the cell membrane. Sterols can bind to its
extracellular cysteine-rich domain (CRD) and to several sites in the seven
transmembrane helices (7-TMs) of SMO. However, the mechanism by which sterols
regulate SMO via multiple sites is unknown. Here we determined the structures of
SMO-Gi complexes bound to the synthetic SMO agonist (SAG) and to
24(S),25-epoxycholesterol (24(S),25-EC). A novel sterol-binding site in the
extracellular extension of TM6 was revealed to connect other sites in 7-TMs and
CRD, forming an intramolecular sterol channel from the middle side of 7-TMs to
CRD. Additional structures of two gain-of-function variants, SMOD384R
and SMOG111C/I496C, showed that blocking the channel at its midpoints
allows sterols to occupy the binding sites in 7-TMs, thereby activating SMO.
These data indicate that sterol transport through the core of SMO is a major
regulator of SMO-mediated signaling.
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