2LSP

solution structures of BRD4 second bromodomain with NF-kB-K310ac peptide

Summary for 2LSP

• Entry DOI: 10.2210/pdb2lsp/pdb
• NMR Information: BMRB: 18439
• Descriptor: NF-kB-K310ac peptide, Bromodomain-containing protein 4 (2 entities in total)
• Functional Keywords: nf-kb, brd4, hiv, bromodomain, kidney disease, protein binding
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: Q04206 O60885
• Total number of polymer chains: 2
• Total formula weight: 16506.01

Authors

Zhang, G.,Liu, R.,Zhong, Y.,Plotnikov, A.N.,Zhang, W.,Rusinova, E.,Gerona-Nevarro, G.,Moshkina, N.,Joshua, J.,Chuang, P.Y.,Ohlmeyer, M.,He, J.,Zhou, M.-M. (deposition date: 2012-05-03, release date: 2012-07-18, Last modification date: 2024-11-06)

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

SOLUTION NMR