PDBsum entry 4f3i

Signaling protein/inhibitor

PDB id: 4f3i

Contents

Protein chain

127 a.a.

Ligands

EDO ×2

0S6

Waters ×184

PDB id:

4f3i

Name:

Signaling protein/inhibitor

Title:

Crystal structure of the first bromodomain of human brd4 in complex with ms417 inhibitor

Structure:

Bromodomain-containing protein 4. Chain: a. Fragment: bromodomain 1 (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: 562

Resolution:

1.40Å R-factor: 0.139 R-free: 0.183

Authors:

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

Key ref:

G.Zhang et al. (2012). Down-regulation of NF-κB transcriptional activity in HIV-associated kidney disease by BRD4 inhibition. J Biol Chem, 287, 28840-28851. PubMed id: 22645123 DOI: 10.1074/jbc.M112.359505

Date:

09-May-12 Release date: 12-Sep-12

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: 10.1074/jbc.M112.359505

J Biol Chem 287:28840-28851 (2012)

PubMed id: 22645123

Down-regulation of NF-κB transcriptional activity in HIV-associated kidney disease by BRD4 inhibition.

G.Zhang, R.Liu, Y.Zhong, A.N.Plotnikov, W.Zhang, L.Zeng, E.Rusinova, G.Gerona-Nevarro, N.Moshkina, J.Joshua, P.Y.Chuang, M.Ohlmeyer, J.C.He, M.M.Zhou.

ABSTRACT

NF-κB-mediated inflammation is the major pathology in chronic kidney diseases, including HIV-associated nephropathy (HIVAN) that ultimately progresses to end stage renal disease. HIV infection in the kidney induces NF-κB activation, leading to the production of proinflammatory chemokines, cytokines, and adhesion molecules. In this study, we explored selective inhibition of NF-κB transcriptional activity by small molecule blocking NF-κB binding to the transcriptional cofactor BRD4, which is required for the assembly of the productive transcriptional complex comprising positive transcription elongation factor b and RNA polymerase II. We showed that our BET (Bromodomain and Extra-Terminal domain)-specific bromodomain inhibitor MS417, designed to block BRD4 binding to the acetylated NF-κB, effectively attenuates NF-κB transcriptional activation of proinflammatory genes in kidney cells treated with TNFα or infected by HIV. MS417 ameliorates inflammation and kidney injury in HIV-1 transgenic mice, an animal model for HIVAN. Our study suggests that BET bromodomain inhibition, targeting at the proinflammatory activity of NF-κB, represents a new therapeutic approach for treating NF-κB-mediated inflammation and kidney injury in HIVAN.