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PDBsum entry 5dw1
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Protein binding/inhibitor
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PDB id
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5dw1
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References listed in PDB file
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Key reference
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Title
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Rvx-297- A novel bd2 selective inhibitor of bet bromodomains.
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Authors
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O.A.Kharenko,
E.M.Gesner,
R.G.Patel,
K.Norek,
A.White,
E.Fontano,
R.K.Suto,
P.R.Young,
K.G.Mclure,
H.C.Hansen.
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Ref.
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Biochem Biophys Res Commun, 2016,
477,
62-67.
[DOI no: ]
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PubMed id
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Abstract
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Bromodomains are epigenetic readers that specifically bind to the acetyl lysine
residues of histones and transcription factors. Small molecule BET bromodomain
inhibitors can disrupt this interaction which leads to potential modulation of
several disease states. Here we describe the binding properties of a novel BET
inhibitor RVX-297 that is structurally related to the clinical compound RVX-208,
currently undergoing phase III clinical trials for the treatment of
cardiovascular diseases, but is distinctly different in its biological and
pharmacokinetic profiles. We report that RVX-297 preferentially binds to the BD2
domains of the BET bromodomain and Extra Terminal (BET) family of protein. We
demonstrate the differential binding modes of RVX-297 in BD1 and BD2 domains of
BRD4 and BRD2 using X-ray crystallography, and describe the structural
differences driving the BD2 selective binding of RVX-297. The isothermal
titration calorimetry (ITC) data illustrate the related differential
thermodynamics of binding of RVX-297 to single as well as dual BET bromodomains.
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