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PDBsum entry 4tu6
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Gene regulation
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PDB id
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4tu6
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References listed in PDB file
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Key reference
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Title
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Observed bromodomain flexibility reveals histone peptide- And small molecule ligand-Compatible forms of atad2.
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Authors
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G.Poncet-Montange,
Y.Zhan,
J.P.Bardenhagen,
A.Petrocchi,
E.Leo,
X.Shi,
G.R.Lee,
P.G.Leonard,
M.K.Geck do,
M.G.Cardozo,
J.N.Andersen,
W.S.Palmer,
P.Jones,
J.E.Ladbury.
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Ref.
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Biochem J, 2015,
466,
337-346.
[DOI no: ]
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PubMed id
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Abstract
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Preventing histone recognition by bromodomains emerges as an attractive
therapeutic approach in cancer. Overexpression of ATAD2 (ATPase family AAA
domain-containing 2 isoform A) in cancer cells is associated with poor prognosis
making the bromodomain of ATAD2 a promising epigenetic therapeutic target. In
the development of an in vitro assay and identification of small molecule
ligands, we conducted structure-guided studies which revealed a conformationally
flexible ATAD2 bromodomain. Structural studies on apo-, peptide-and small
molecule-ATAD2 complexes (by co-crystallization) revealed that the bromodomain
adopts a 'closed', histone-compatible conformation and a more 'open'
ligand-compatible conformation of the binding site respectively. An unexpected
conformational change of the conserved asparagine residue plays an important
role in driving the peptide-binding conformation remodelling. We also identified
dimethylisoxazole-containing ligands as ATAD2 binders which aided in the
validation of the in vitro screen and in the analysis of these conformational
studies.
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