4F3I

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

Summary for 4F3I

• Entry DOI: 10.2210/pdb4f3i/pdb
• Descriptor: Bromodomain-containing protein 4, 1,2-ETHANEDIOL, methyl [(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, ... (4 entities in total)
• Functional Keywords: protein-inhibitor complex, acetyl-lysine binding, nucleus, signaling protein-inhibitor complex, signaling protein/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 1
• Total formula weight: 15638.42

Authors

Joshua, J.,Zhou, M.-M.,Plotnikov, A.N. (deposition date: 2012-05-09, release date: 2012-09-12, Last modification date: 2023-09-13)

Primary citation

Zhang, G.,Liu, R.,Zhong, Y.,Plotnikov, A.N.,Zhang, W.,Zeng, L.,Rusinova, E.,Gerona-Nevarro, G.,Moshkina, N.,Joshua, J.,Chuang, P.Y.,Ohlmeyer, M.,He, J.C.,Zhou, M.M.
Down-regulation of NF-{kappa}B Transcriptional Activity in HIV-associated Kidney Disease by BRD4 Inhibition.
J.Biol.Chem., 287:28840-28851, 2012

PubMed 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.

PubMed: 22645123
DOI: 10.1074/jbc.M112.359505

Experimental method

X-RAY DIFFRACTION (1.4 Å)