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PDBsum entry 5dnm
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Structural protein/DNA
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PDB id
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5dnm
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Contents |
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97 a.a.
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82 a.a.
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106 a.a.
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95 a.a.
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87 a.a.
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References listed in PDB file
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Key reference
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Title
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Allosteric cross-Talk in chromatin can mediate drug-Drug synergy.
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Authors
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Z.Adhireksan,
G.Palermo,
T.Riedel,
Z.Ma,
R.Muhammad,
U.Rothlisberger,
P.J.Dyson,
C.A.Davey.
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Ref.
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Nat Commun, 2017,
8,
14860.
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PubMed id
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Abstract
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Exploitation of drug-drug synergism and allostery could yield superior therapies
by capitalizing on the immensely diverse, but highly specific, potential
associated with the biological macromolecular landscape. Here we describe a
drug-drug synergy mediated by allosteric cross-talk in chromatin, whereby the
binding of one drug alters the activity of the second. We found two unrelated
drugs, RAPTA-T and auranofin, that yield a synergistic activity in killing
cancer cells, which coincides with a substantially greater number of chromatin
adducts formed by one of the compounds when adducts from the other agent are
also present. We show that this occurs through an allosteric mechanism within
the nucleosome, whereby defined histone adducts of one drug promote reaction of
the other drug at a distant, specific histone site. This opens up possibilities
for epigenetic targeting and suggests that allosteric modulation in nucleosomes
may have biological relevance and potential for therapeutic interventions.
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