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PDBsum entry 4pl5
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Transferase,hydrolase/inhibitor
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PDB id
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4pl5
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References listed in PDB file
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Key reference
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Title
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Structure and mechanism of action of the hydroxy-Aryl-Aldehyde class of ire1 endoribonuclease inhibitors.
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Authors
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M.Sanches,
N.M.Duffy,
M.Talukdar,
N.Thevakumaran,
D.Chiovitti,
M.D.Canny,
K.Lee,
I.Kurinov,
D.Uehling,
R.Al-Awar,
G.Poda,
M.Prakesch,
B.Wilson,
V.Tam,
C.Schweitzer,
A.Toro,
J.L.Lucas,
D.Vuga,
L.Lehmann,
D.Durocher,
Q.Zeng,
J.B.Patterson,
F.Sicheri.
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Ref.
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Nat Commun, 2014,
5,
4202.
[DOI no: ]
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PubMed id
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Abstract
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Endoplasmic reticulum (ER) stress activates the unfolded protein response and
its dysfunction is linked to multiple diseases. The stress transducer IRE1α is
a transmembrane kinase endoribonuclease (RNase) that cleaves mRNA substrates to
re-establish ER homeostasis. Aromatic ring systems containing hydroxy-aldehyde
moieties, termed hydroxy-aryl-aldehydes (HAA), selectively inhibit IRE1α RNase
and thus represent a novel chemical series for therapeutic development. We
solved crystal structures of murine IRE1α in complex with three HAA inhibitors.
HAA inhibitors engage a shallow pocket at the RNase-active site through
pi-stacking interactions with His910 and Phe889, an essential Schiff base with
Lys907 and a hydrogen bond with Tyr892. Structure-activity studies and
mutational analysis of contact residues define the optimal chemical space of
inhibitors and validate the inhibitor-binding site. These studies lay the
foundation for understanding both the biochemical and cellular functions of
IRE1α using small molecule inhibitors and suggest new avenues for inhibitor
design.
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