PDBsum entry 4o7e

Transcription/inhibitor

PDB id: 4o7e

Contents

Protein chains

127 a.a.

Ligands

2RN ×4

EDO ×3

Waters ×230

PDB id:

4o7e

Name:

Transcription/inhibitor

Title:

Crystal structure of the first bromodomain of human brd4 in complex with sb-610251-b

Structure:

Bromodomain-containing protein 4. Chain: a, b. Fragment: unp residues 44-168. Synonym: protein hunk1. Engineered: yes

Source:

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

Resolution:

1.85Å R-factor: 0.157 R-free: 0.210

Authors:

S.W.Ember,J.-Y.Zhu,C.Watts,E.Schonbrunn

Key ref:

S.W.Ember et al. (2014). Acetyl-lysine binding site of bromodomain-containing protein 4 (BRD4) interacts with diverse kinase inhibitors. Acs Chem Biol, 9, 1160-1171. PubMed id: 24568369 DOI: 10.1021/cb500072z

Date:

24-Dec-13 Release date: 05-Mar-14

Protein chains

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: 10.1021/cb500072z

Acs Chem Biol 9:1160-1171 (2014)

PubMed id: 24568369

Acetyl-lysine binding site of bromodomain-containing protein 4 (BRD4) interacts with diverse kinase inhibitors.

S.W.Ember, J.Y.Zhu, S.H.Olesen, M.P.Martin, A.Becker, N.Berndt, G.I.Georg, E.Schönbrunn.

ABSTRACT

Members of the bromodomain and extra terminal (BET) family of proteins are essential for the recognition of acetylated lysine (KAc) residues in histones and have emerged as promising drug targets in cancer, inflammation, and contraception research. In co-crystallization screening campaigns using the first bromodomain of BRD4 (BRD4-1) against kinase inhibitor libraries, we identified and characterized 14 kinase inhibitors (10 distinct chemical scaffolds) as ligands of the KAc binding site. Among these, the PLK1 inhibitor BI2536 and the JAK2 inhibitor TG101209 displayed strongest inhibitory potential against BRD4 (IC50 = 25 nM and 130 nM, respectively) and high selectivity for BET bromodomains. Comparative structural analysis revealed markedly different binding modes of kinase hinge-binding scaffolds in the KAc binding site, suggesting that BET proteins are potential off-targets of diverse kinase inhibitors. Combined, these findings provide a new structural framework for the rational design of next-generation BET-selective and dual-activity BET-kinase inhibitors.