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@ARTICLE{Yokoyama:872856,
author = {Yokoyama, Takeshi and Matsumoto, Kazunori and Ostermann,
Andreas and Schrader, Tobias E. and Nabeshima, Yuko and
Mizuguchi, Mineyuki},
title = {{S}tructural and thermodynamic characterization of the
binding of isoliquiritigenin to the first bromodomain of
{BRD}4},
journal = {The FEBS journal},
volume = {286},
number = {9},
issn = {1742-4658},
address = {Oxford [u.a.]},
publisher = {Wiley-Blackwell},
reportid = {FZJ-2020-00324},
pages = {1656 - 1667},
year = {2019},
abstract = {Bromodomain-containing protein 4 (BRD4) recognizes the
acetylated lysineof histone H4 via its bromodomains, leading
to the recruitment of positivetranscription elongation
factor b. Small molecules that inhibit BRD4 havepotential as
anticancer agents by leading to the downregulation of
specificoncogenes. Using X-ray crystallographic screening,
we identified the BRD4inhibitory activity of
isoliquiritigenin (ISL), a natural chalcone found
inlicorice. Structural analysis revealed that ISL bound to
BRD4 with a novelbinding mode and squeezed out one of the
six conserved water moleculesthat form a strong hydrogen
bond network. The thermodynamic analysisrevealed that the
binding of ISL is enthalpy driven, suggesting that
stronghydrogen bonds would compensate for the desolvation
penalty. Neutronprotein crystallography further suggested
that the favorable bindingenthalpy originates from the
stabilization and optimization of the hydrogenbond network
of the conserved water molecules. Here, we describe the
noveltyand potential of ISL as a template for new BRD4
inhibitors.},
cin = {JCNS-FRM-II / JCNS-1 / MLZ},
ddc = {610},
cid = {I:(DE-Juel1)JCNS-FRM-II-20110218 /
I:(DE-Juel1)JCNS-1-20110106 / I:(DE-588b)4597118-3},
pnm = {6G4 - Jülich Centre for Neutron Research (JCNS) (POF3-623)
/ 6G15 - FRM II / MLZ (POF3-6G15) / 6215 - Soft Matter,
Health and Life Sciences (POF3-621)},
pid = {G:(DE-HGF)POF3-6G4 / G:(DE-HGF)POF3-6G15 /
G:(DE-HGF)POF3-6215},
experiment = {EXP:(DE-MLZ)BIODIFF-20140101},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:30565859},
UT = {WOS:000467253400005},
doi = {10.1111/febs.14736},
url = {https://juser.fz-juelich.de/record/872856},
}