PDBsum entry 4qb3

Transcription/transcription inhibitor

PDB id: 4qb3

Contents

Protein chain

127 a.a.

Ligands

30M

EDO

Waters ×289

PDB id:

4qb3

Name:

Transcription/transcription inhibitor

Title:

Crystal structure of the first bromodomain of human brd4 in complex with olinone

Structure:

Bromodomain-containing protein 4. Chain: a. Synonym: protein hunk1. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: brd4, hunk1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

0.94Å R-factor: 0.137 R-free: 0.155

Authors:

A.N.Plotnikov,J.Joshua,M.-M.Zhou

Key ref:

M.Gacias et al. (2014). Selective chemical modulation of gene transcription favors oligodendrocyte lineage progression. Chem Biol, 21, 841-854. PubMed id: 24954007 DOI: 10.1016/j.chembiol.2014.05.009

Date:

06-May-14 Release date: 22-Apr-15

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)

DOI no: 10.1016/j.chembiol.2014.05.009

Chem Biol 21:841-854 (2014)

PubMed id: 24954007

Selective chemical modulation of gene transcription favors oligodendrocyte lineage progression.

M.Gacias, G.Gerona-Navarro, A.N.Plotnikov, G.Zhang, L.Zeng, J.Kaur, G.Moy, E.Rusinova, Y.Rodriguez, B.Matikainen, A.Vincek, J.Joshua, P.Casaccia, M.M.Zhou.

ABSTRACT

Lysine acetylation regulates gene expression through modulating protein-protein interactions in chromatin. Chemical inhibition of acetyl-lysine binding bromodomains of the major chromatin regulators BET (bromodomain and extraterminal domain) proteins has been shown to effectively block cell proliferation in cancer and inflammation. However, whether selective inhibition of individual BET bromodomains has distinctive functional consequences remains only partially understood. In this study, we show that selective chemical inhibition of the first bromodomain of BET proteins using our small-molecule inhibitor, Olinone, accelerated the progression of mouse primary oligodendrocyte progenitors toward differentiation, whereas inhibition of both bromodomains of BET proteins hindered differentiation. This effect was target specific, as it was not detected in cells treated with inactive analogs and independent of any effect on proliferation. Therefore, selective chemical modulation of individual bromodomains, rather than use of broad-based inhibitors, may enhance regenerative strategies in disorders characterized by myelin loss such as aging and neurodegeneration.