5DW2

X-ray crystal structure of human BRD4(BD1) in complex with RVX297 to 1.12 A resolution

Summary for 5DW2

• Entry DOI: 10.2210/pdb5dw2/pdb
• Related: 5DW1
• Descriptor: Bromodomain-containing protein 4, 2-{3,5-dimethyl-4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-5,7-dimethoxyquinazolin-4(3H)-one, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: bromodomain, protein binding-inhibitor complex, protein binding/inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 1
• Total formula weight: 16001.38

Authors

White, A.,Fontano, E.,Suto, R.K. (deposition date: 2015-09-22, release date: 2016-06-22, Last modification date: 2024-03-06)

Primary citation

Kharenko, O.A.,Gesner, E.M.,Patel, R.G.,Norek, K.,White, A.,Fontano, E.,Suto, R.K.,Young, P.R.,McLure, K.G.,Hansen, H.C.
RVX-297- a novel BD2 selective inhibitor of BET bromodomains.
Biochem.Biophys.Res.Commun., 477:62-67, 2016

PubMed Abstract: 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.

PubMed: 27282480
DOI: 10.1016/j.bbrc.2016.06.021

Experimental method

X-RAY DIFFRACTION (1.12 Å)