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PDBsum entry 3bl7
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References listed in PDB file
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Key reference
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Title
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Dcps as a therapeutic target for spinal muscular atrophy.
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Authors
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J.Singh,
M.Salcius,
S.W.Liu,
B.L.Staker,
R.Mishra,
J.Thurmond,
G.Michaud,
D.R.Mattoon,
J.Printen,
J.Christensen,
J.M.Bjornsson,
B.A.Pollok,
M.Kiledjian,
L.Stewart,
J.Jarecki,
M.E.Gurney.
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Ref.
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Acs Chem Biol, 2008,
3,
711-722.
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PubMed id
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Abstract
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Spinal muscular atrophy (SMA) is caused by deletion or mutation of both copies
of the SMN1 gene, which produces an essential protein known as SMN. The severity
of SMA is modified by variable copy number of a second gene,SMN2, which produces
an mRNA that is incorrectly spliced with deletion of the last exon. We described
previously the discovery of potent C5-substituted quinazolines that increase
SMN2 gene expression by 2-fold. Discovery of potent SMN2 promoter inducers
relied on a cellular assay without knowledge of the molecular target. Using
protein microarray scanning with a radiolabeled C5-substituted quinazoline
probe, we identified the scavenger decapping enzyme, DcpS, as a potential
binder. We show that the C5-substituted quinazolines potently inhibit DcpS
decapping activity and that the potency of inhibition correlates with potency
forSMN2 promoter induction. Binding of C5-substituted quinazolines to DcpS holds
the enzyme in an open, catalytically incompetent conformation. DcpS is a nuclear
shuttling protein that binds and hydrolyzes the m(7)GpppN mRNA cap structure and
a modulator of RNA metabolism. Therefore DcpS represents a novel therapeutic
target for modulating gene expression by a small molecule.
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