4F3I: Crystal structure of the first bromodomain of human BRD4 in complex with MS417 inhibitor

NF-kappaB-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-kappaB activation, leading to the production of proinflammatory chemokines, cytokines, and adhesion molecules. In this study, we explored selective inhibition of NF-kappaB transcriptional activity by small molecule blocking NF-kappaB 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-kappaB, effectively attenuates NF-kappaB transcriptional activation of proinflammatory genes in kidney cells treated with TNFalpha 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-kappaB, represents a new therapeutic approach for treating NF-kappaB-mediated inflammation and kidney injury in HIVAN.
PDB ID: 4F3IDownload
MMDB ID: 102865
PDB Deposition Date: 2012/5/9
Updated in MMDB: 2012/09
Experimental Method:
x-ray diffraction
Resolution: 1.4  Å
Source Organism:
Similar Structures:
Biological Unit for 4F3I: monomeric; determined by author and by software (PISA)
Molecular Components in 4F3I
Label Count Molecule
Protein (1 molecule)
Bromodomain-containing Protein 4(Gene symbol: BRD4)
Molecule annotation
Chemicals (3 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB