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PDBsum entry 5ivc
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Oxidoreductase/oxidoreductase inhibitor
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PDB id
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5ivc
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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 for kdm5a histone lysine demethylase inhibition by diverse compounds.
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Authors
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J.R.Horton,
X.Liu,
M.Gale,
L.Wu,
J.R.Shanks,
X.Zhang,
P.J.Webber,
J.S.Bell,
S.C.Kales,
B.T.Mott,
G.Rai,
D.J.Jansen,
M.J.Henderson,
D.J.Urban,
M.D.Hall,
A.Simeonov,
D.J.Maloney,
M.A.Johns,
H.Fu,
A.Jadhav,
P.M.Vertino,
Q.Yan,
X.Cheng.
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Ref.
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Cell Chem Biol, 2016,
23,
769-781.
[DOI no: ]
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PubMed id
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Abstract
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The KDM5/JARID1 family of Fe(II)- and α-ketoglutarate-dependent demethylases
removes methyl groups from methylated lysine 4 of histone H3. Accumulating
evidence supports a role for KDM5 family members as oncogenic drivers. We
compare the in vitro inhibitory properties and binding affinity of ten diverse
compounds with all four family members, and present the crystal structures of
the KDM5A-linked Jumonji domain in complex with eight of these inhibitors in the
presence of Mn(II). All eight inhibitors structurally examined occupy the
binding site of α-ketoglutarate, but differ in their specific binding
interactions, including the number of ligands involved in metal coordination. We
also observed inhibitor-induced conformational changes in KDM5A, particularly
those residues involved in the binding of α-ketoglutarate, the anticipated
peptide substrate, and intramolecular interactions. We discuss how particular
chemical moieties contribute to inhibitor potency and suggest strategies that
might be utilized in the successful design of selective and potent epigenetic
inhibitors.
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Secondary reference #1
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Title
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Characterization of a linked jumonji domain of the kdm5/jarid1 family of histone h3 lysine 4 demethylases.
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Authors
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J.R.Horton,
A.Engstrom,
E.L.Zoeller,
X.Liu,
J.R.Shanks,
X.Zhang,
M.A.Johns,
P.M.Vertino,
H.Fu,
X.Cheng.
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Ref.
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J Biol Chem, 2016,
291,
2631-2646.
[DOI no: ]
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PubMed id
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