PDBsum entry 5dw2

Protein binding/inhibitor

PDB id: 5dw2

Contents

Protein chain

127 a.a.

Ligands

5GD

EDO ×4

Waters ×295

PDB id:

5dw2

Name:

Protein binding/inhibitor

Title:

X-ray crystal structure of human brd4(bd1) in complex with rvx297 to 1.12 a resolution

Structure:

Bromodomain-containing protein 4. Chain: a. Fragment: unp residues 44-170. Synonym: protein hunk1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: brd4, hunk1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

1.12Å R-factor: 0.124 R-free: 0.151

Authors:

A.White,E.Fontano,R.K.Suto

Key ref:

O.A.Kharenko et al. (2016). RVX-297- a novel BD2 selective inhibitor of BET bromodomains. Biochem Biophys Res Commun, 477, 62-67. PubMed id: 27282480 DOI: 10.1016/j.bbrc.2016.06.021

Date:

22-Sep-15 Release date: 22-Jun-16

Protein chain

O60885  (BRD4_HUMAN) -  Bromodomain-containing protein 4 from Homo sapiens

Seq: 1362 a.a.

Struc: 127 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1016/j.bbrc.2016.06.021

Biochem Biophys Res Commun 477:62-67 (2016)

PubMed id: 27282480

RVX-297- a novel BD2 selective inhibitor of BET bromodomains.

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.

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.