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PDBsum entry 4f3i
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Signaling protein/inhibitor
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PDB id
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4f3i
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References listed in PDB file
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Key reference
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Title
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Down-Regulation of nf-κB transcriptional activity in HIV-Associated kidney disease by brd4 inhibition.
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Authors
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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.
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Ref.
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J Biol Chem, 2012,
287,
28840-28851.
[DOI no: ]
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PubMed id
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Abstract
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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.
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