2lsp

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{{STRUCTURE_2lsp| PDB=2lsp | SCENE= }}
 
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===solution structures of BRD4 second bromodomain with NF-kB-K310ac peptide===
 
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==Disease==
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==solution structures of BRD4 second bromodomain with NF-kB-K310ac peptide==
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[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.<ref>PMID:12543779</ref><ref>PMID:11733348</ref>
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<StructureSection load='2lsp' size='340' side='right'caption='[[2lsp]]' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2lsp]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2LSP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2LSP FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 20 models</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ALY:N(6)-ACETYLLYSINE'>ALY</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2lsp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2lsp OCA], [https://pdbe.org/2lsp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2lsp RCSB], [https://www.ebi.ac.uk/pdbsum/2lsp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2lsp ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/TF65_HUMAN TF65_HUMAN] NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and p65-c-Rel complexes are transcriptional activators. The NF-kappa-B p65-p65 complex appears to be involved in invasin-mediated activation of IL-8 expression. The inhibitory effect of I-kappa-B upon NF-kappa-B the cytoplasm is exerted primarily through the interaction with p65. p65 shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex. Associates with chromatin at the NF-kappa-B promoter region via association with DDX1.<ref>PMID:10928981</ref> <ref>PMID:12748188</ref> <ref>PMID:17000776</ref> <ref>PMID:17620405</ref> <ref>PMID:19058135</ref> <ref>PMID:20547752</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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==Function==
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Down-regulation of NF-kappaB Transcriptional Activity in HIV-associated Kidney Disease by BRD4 Inhibition.,Zhang G, Liu R, Zhong Y, Plotnikov AN, Zhang W, Zeng L, Rusinova E, Gerona-Nevarro G, Moshkina N, Joshua J, Chuang PY, Ohlmeyer M, He JC, Zhou MM J Biol Chem. 2012 Aug 17;287(34):28840-51. Epub 2012 May 29. PMID:22645123<ref>PMID:22645123</ref>
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[[http://www.uniprot.org/uniprot/TF65_HUMAN TF65_HUMAN]] NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and p65-c-Rel complexes are transcriptional activators. The NF-kappa-B p65-p65 complex appears to be involved in invasin-mediated activation of IL-8 expression. The inhibitory effect of I-kappa-B upon NF-kappa-B the cytoplasm is exerted primarily through the interaction with p65. p65 shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex. Associates with chromatin at the NF-kappa-B promoter region via association with DDX1.<ref>PMID:10928981</ref><ref>PMID:12748188</ref><ref>PMID:17000776</ref><ref>PMID:17620405</ref><ref>PMID:19058135</ref><ref>PMID:20547752</ref> [[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[2lsp]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2LSP OCA].
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</div>
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<div class="pdbe-citations 2lsp" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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<references group="xtra"/><references/>
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*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Chuang, P Y.]]
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[[Category: Large Structures]]
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[[Category: Gerona-Nevarro, G.]]
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[[Category: Chuang PY]]
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[[Category: He, J.]]
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[[Category: Gerona-Nevarro G]]
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[[Category: Joshua, J.]]
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[[Category: He J]]
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[[Category: Liu, R.]]
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[[Category: Joshua J]]
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[[Category: Moshkina, N.]]
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[[Category: Liu R]]
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[[Category: Ohlmeyer, M.]]
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[[Category: Moshkina N]]
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[[Category: Plotnikov, A N.]]
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[[Category: Ohlmeyer M]]
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[[Category: Rusinova, E.]]
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[[Category: Plotnikov AN]]
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[[Category: Zhang, G.]]
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[[Category: Rusinova E]]
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[[Category: Zhang, W.]]
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[[Category: Zhang G]]
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[[Category: Zhong, Y.]]
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[[Category: Zhang W]]
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[[Category: Zhou, M M.]]
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[[Category: Zhong Y]]
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[[Category: Brd4]]
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[[Category: Zhou M-M]]
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[[Category: Bromodomain]]
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[[Category: Hiv]]
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[[Category: Kidney disease]]
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[[Category: Nf-kb]]
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[[Category: Protein binding]]
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Current revision

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

PDB ID 2lsp

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