PDBsum entry 4cfl

Cell cycle

PDB id: 4cfl

Contents

Protein chain

127 a.a.

Ligands

8DQ

EDO

GOL

Waters ×289

PDB id:

4cfl

Name:

Cell cycle

Title:

N-terminal bromodomain of human brd4 with ly303511

Structure:

Brd4 protein. Chain: a. Fragment: n-terminal bromodomain, residues 42-168. Synonym: bromodomain containing protein 4. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.32Å R-factor: 0.191 R-free: 0.217

Authors:

C.Chung,A.Dittmann,G.Drewes

Key ref:

A.Dittmann et al. (2014). The commonly used PI3-kinase probe LY294002 is an inhibitor of BET bromodomains. Acs Chem Biol, 9, 495-502. PubMed id: 24533473 DOI: 10.1021/cb400789e

Date:

18-Nov-13 Release date: 15-Jan-14

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: 10.1021/cb400789e

Acs Chem Biol 9:495-502 (2014)

PubMed id: 24533473

The commonly used PI3-kinase probe LY294002 is an inhibitor of BET bromodomains.

A.Dittmann, T.Werner, C.W.Chung, M.M.Savitski, M.Fälth Savitski, P.Grandi, C.Hopf, M.Lindon, G.Neubauer, R.K.Prinjha, M.Bantscheff, G.Drewes.

ABSTRACT

A commonly used small-molecule probe in cell-signaling research is the phosphoinositide 3-kinase inhibitor LY294002. Quantitative chemoproteomic profiling shows that LY294002 and LY303511, a close analogue devoid of PI3K activity, inhibit the BET bromodomain proteins BRD2, BRD3, and BRD4 that comprise a family of targets structurally unrelated to PI3K. Both compounds competitively inhibit acetyl-lysine binding of the first but not the second bromodomain of BET proteins in cell extracts. X-ray crystallography shows that the chromen-4-one scaffold represents a new bromodomain pharmacophore and establishes LY294002 as a dual kinase and BET-bromodomain inhibitor, whereas LY303511 exhibits anti-inflammatory and antiproliferative effects similar to the recently discovered BET inhibitors.