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PDBsum entry 6htt
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References listed in PDB file
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Key reference
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Title
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Characterization of histone deacetylase 8 (hdac8) selective inhibition reveals specific active site structural and functional determinants.
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Authors
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M.Marek,
T.B.Shaik,
T.Heimburg,
A.Chakrabarti,
J.Lancelot,
E.Ramos-Morales,
C.Da veiga,
D.Kalinin,
J.Melesina,
D.Robaa,
K.Schmidtkunz,
T.Suzuki,
R.Holl,
E.Ennifar,
R.J.Pierce,
M.Jung,
W.Sippl,
C.Romier.
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Ref.
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J Med Chem, 2018,
61,
10000-10016.
[DOI no: ]
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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Abstract
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Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that
represent promising therapeutic targets for the treatment of numerous human
diseases. Yet the currently FDA-approved HDAC inhibitors nonspecifically target
at least several of the 11 structurally similar but functionally different HDAC
isozymes, which hampers their broad usage in clinical settings. Selective
inhibitors targeting single HDAC isozymes are being developed, but precise
understanding in molecular terms of their selectivity remains sparse. Here, we
show that HDAC8-selective inhibitors adopt a L-shaped conformation required for
their binding to a HDAC8-specific pocket formed by HDAC8 catalytic tyrosine and
HDAC8 L1 and L6 loops. In other HDAC isozymes, a L1-L6 lock sterically prevents
L-shaped inhibitor binding. Shielding of the HDAC8-specific pocket by protein
engineering decreases potency of HDAC8-selective inhibitors and affects
catalytic activity. Collectively, our results unravel key HDAC8 active site
structural and functional determinants important for the design of
next-generation chemical probes and epigenetic drugs.
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