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6v17

From Proteopedia

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Current revision

Crystal structure of the bromodomain of human BRD7 bound to I-BRD9

Structural highlights

6v17 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.05Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

BRD7_HUMAN Acts both as coactivator and as corepressor. May play a role in chromatin remodeling. Activator of the Wnt signaling pathway in a DVL1-dependent manner by negatively regulating the GSK3B phosphotransferase activity. Induces dephosphorylation of GSK3B at 'Tyr-216'. Down-regulates TRIM24-mediated activation of transcriptional activation by AR (By similarity). Transcriptional corepressor that down-regulates the expression of target genes. Binds to target promoters, leading to increased histone H3 acetylation at 'Lys-9' (H3K9ac). Binds to the ESR1 promoter. Recruits BRCA1 and POU2F1 to the ESR1 promoter. Coactivator for TP53-mediated activation of transcription of a set of target genes. Required for TP53-mediated cell-cycle arrest in response to oncogene activation. Promotes acetylation of TP53 at 'Lys-382', and thereby promotes efficient recruitment of TP53 to target promoters. Inhibits cell cycle progression from G1 to S phase.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

Inhibition of the bromodomain containing protein 9 (BRD9) by small molecules is an attractive strategy to target mutated SWI/SNF chromatin-remodeling complexes in cancer. However, reported BRD9 inhibitors also inhibit the closely related bromodomain-containing protein 7 (BRD7), which has different biological functions. The structural basis for differential potency and selectivity of BRD9 inhibitors is largely unknown because of the lack of structural information on BRD7. Here, we biochemically and structurally characterized diverse inhibitors with varying degrees of potency and selectivity for BRD9 over BRD7. Novel cocrystal structures of BRD7 liganded with new and previously reported inhibitors of five different chemical scaffolds were determined alongside BRD9 and BRD4. We also report the discovery of first-in-class dual bromodomain-kinase inhibitors outside the bromodomain and extraterminal family targeting BRD7 and BRD9. Combined, the data provide a new framework for the development of BRD7/9 inhibitors with improved selectivity or additional polypharmacologic properties.

Structural Basis of Inhibitor Selectivity in the BRD7/9 Subfamily of Bromodomains.,Karim RM, Chan A, Zhu JY, Schonbrunn E J Med Chem. 2020 Mar 6. doi: 10.1021/acs.jmedchem.9b01980. PMID:32091206^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Peng C, Zhou J, Liu HY, Zhou M, Wang LL, Zhang QH, Yang YX, Xiong W, Shen SR, Li XL, Li GY. The transcriptional regulation role of BRD7 by binding to acetylated histone through bromodomain. J Cell Biochem. 2006 Mar 1;97(4):882-92. PMID:16265664 doi:http://dx.doi.org/10.1002/jcb.20645
↑ Zhou M, Liu H, Xu X, Zhou H, Li X, Peng C, Shen S, Xiong W, Ma J, Zeng Z, Fang S, Nie X, Yang Y, Zhou J, Xiang J, Cao L, Peng S, Li S, Li G. Identification of nuclear localization signal that governs nuclear import of BRD7 and its essential roles in inhibiting cell cycle progression. J Cell Biochem. 2006 Jul 1;98(4):920-30. PMID:16475162 doi:http://dx.doi.org/10.1002/jcb.20788
↑ Harte MT, O'Brien GJ, Ryan NM, Gorski JJ, Savage KI, Crawford NT, Mullan PB, Harkin DP. BRD7, a subunit of SWI/SNF complexes, binds directly to BRCA1 and regulates BRCA1-dependent transcription. Cancer Res. 2010 Mar 15;70(6):2538-47. doi: 10.1158/0008-5472.CAN-09-2089. Epub, 2010 Mar 9. PMID:20215511 doi:http://dx.doi.org/10.1158/0008-5472.CAN-09-2089
↑ Drost J, Mantovani F, Tocco F, Elkon R, Comel A, Holstege H, Kerkhoven R, Jonkers J, Voorhoeve PM, Agami R, Del Sal G. BRD7 is a candidate tumour suppressor gene required for p53 function. Nat Cell Biol. 2010 Apr;12(4):380-9. doi: 10.1038/ncb2038. Epub 2010 Mar 14. PMID:20228809 doi:http://dx.doi.org/10.1038/ncb2038
↑ Burrows AE, Smogorzewska A, Elledge SJ. Polybromo-associated BRG1-associated factor components BRD7 and BAF180 are critical regulators of p53 required for induction of replicative senescence. Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14280-5. doi:, 10.1073/pnas.1009559107. Epub 2010 Jul 26. PMID:20660729 doi:http://dx.doi.org/10.1073/pnas.1009559107
↑ Karim RM, Chan A, Zhu JY, Schonbrunn E. Structural Basis of Inhibitor Selectivity in the BRD7/9 Subfamily of Bromodomains. J Med Chem. 2020 Mar 6. doi: 10.1021/acs.jmedchem.9b01980. PMID:32091206 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b01980

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6v17"

Categories: Homo sapiens | Large Structures | Chan A | Karim MR | Schonbrunn E

@@ Line 3: / Line 3: @@
 <StructureSection load='6v17' size='340' side='right'caption='[[6v17]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6v17]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6V17 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6V17 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6v17]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6V17 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6V17 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=H1B:N-[1,1-BIS(OXIDANYLIDENE)THIAN-4-YL]-5-ETHYL-4-OXIDANYLIDENE-7-[3-(TRIFLUOROMETHYL)PHENYL]THIENO[3,2-C]PYRIDINE-2-CARBOXIMIDAMIDE'>H1B</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.05&#8491;</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6v17 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6v17 OCA], [http://pdbe.org/6v17 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6v17 RCSB], [http://www.ebi.ac.uk/pdbsum/6v17 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6v17 ProSAT]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=H1B:N-[1,1-BIS(OXIDANYLIDENE)THIAN-4-YL]-5-ETHYL-4-OXIDANYLIDENE-7-[3-(TRIFLUOROMETHYL)PHENYL]THIENO[3,2-C]PYRIDINE-2-CARBOXIMIDAMIDE'>H1B</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6v17 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6v17 OCA], [https://pdbe.org/6v17 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6v17 RCSB], [https://www.ebi.ac.uk/pdbsum/6v17 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6v17 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/BRD7_HUMAN BRD7_HUMAN]] Acts both as coactivator and as corepressor. May play a role in chromatin remodeling. Activator of the Wnt signaling pathway in a DVL1-dependent manner by negatively regulating the GSK3B phosphotransferase activity. Induces dephosphorylation of GSK3B at 'Tyr-216'. Down-regulates TRIM24-mediated activation of transcriptional activation by AR (By similarity). Transcriptional corepressor that down-regulates the expression of target genes. Binds to target promoters, leading to increased histone H3 acetylation at 'Lys-9' (H3K9ac). Binds to the ESR1 promoter. Recruits BRCA1 and POU2F1 to the ESR1 promoter. Coactivator for TP53-mediated activation of transcription of a set of target genes. Required for TP53-mediated cell-cycle arrest in response to oncogene activation. Promotes acetylation of TP53 at 'Lys-382', and thereby promotes efficient recruitment of TP53 to target promoters. Inhibits cell cycle progression from G1 to S phase.<ref>PMID:16265664</ref> <ref>PMID:16475162</ref> <ref>PMID:20215511</ref> <ref>PMID:20228809</ref> <ref>PMID:20660729</ref>
+[https://www.uniprot.org/uniprot/BRD7_HUMAN BRD7_HUMAN] Acts both as coactivator and as corepressor. May play a role in chromatin remodeling. Activator of the Wnt signaling pathway in a DVL1-dependent manner by negatively regulating the GSK3B phosphotransferase activity. Induces dephosphorylation of GSK3B at 'Tyr-216'. Down-regulates TRIM24-mediated activation of transcriptional activation by AR (By similarity). Transcriptional corepressor that down-regulates the expression of target genes. Binds to target promoters, leading to increased histone H3 acetylation at 'Lys-9' (H3K9ac). Binds to the ESR1 promoter. Recruits BRCA1 and POU2F1 to the ESR1 promoter. Coactivator for TP53-mediated activation of transcription of a set of target genes. Required for TP53-mediated cell-cycle arrest in response to oncogene activation. Promotes acetylation of TP53 at 'Lys-382', and thereby promotes efficient recruitment of TP53 to target promoters. Inhibits cell cycle progression from G1 to S phase.<ref>PMID:16265664</ref> <ref>PMID:16475162</ref> <ref>PMID:20215511</ref> <ref>PMID:20228809</ref> <ref>PMID:20660729</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 18: / Line 19: @@
 </div>
 <div class="pdbe-citations 6v17" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Chan, A]]
+[[Category: Chan A]]
-[[Category: Karim, M R]]
+[[Category: Karim MR]]
-[[Category: Schonbrunn, E]]
+[[Category: Schonbrunn E]]
-[[Category: Bp75]]
-[[Category: Bromodomain]]
-[[Category: Celtix1]]
-[[Category: Gene regulation]]
-[[Category: Mswi/snf]]
-[[Category: Non-bet]]
-[[Category: Pbaf]]

6v17

From Proteopedia

Current revision

Crystal structure of the bromodomain of human BRD7 bound to I-BRD9

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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