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==Crystal Structure of BAZ2A bromodomain in complex with 1-methylpyridinone compound 2== | |||
<StructureSection load='6fgf' size='340' side='right' caption='[[6fgf]], [[Resolution|resolution]] 2.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6fgf]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FGF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FGF FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EN2:~{N}-[3-[(4-fluorophenyl)carbonylamino]propyl]-1-methyl-6-oxidanylidene-pyridine-3-carboxamide'>EN2</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6fg6|6fg6]]</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=6fgf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fgf OCA], [http://pdbe.org/6fgf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fgf RCSB], [http://www.ebi.ac.uk/pdbsum/6fgf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fgf ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/BAZ2A_HUMAN BAZ2A_HUMAN]] Essential component of the NoRC (nucleolar remodeling complex) complex, a complex that mediates silencing of a fraction of rDNA by recruiting histone-modifying enzymes and DNA methyltransferases, leading to heterochromatin formation and transcriptional silencing. In the complex, it plays a central role by being recruited to rDNA and by targeting chromatin modifying enzymes such as HDAC1, leading to repress RNA polymerase I transcription. Recruited to rDNA via its interaction with TTF1 and its ability to recognize and bind histone H4 acetylated on 'Lys-16' (H4K16ac), leading to deacetylation of H4K5ac, H4K8ac, H4K12ac but not H4K16ac. Specifically binds pRNAs, 150-250 nucleotide RNAs that are complementary in sequence to the rDNA promoter; pRNA-binding is required for heterochromatin formation and rDNA silencing (By similarity). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The bromodomain-containing protein BAZ2A is a validated target in prostate cancer, while the function of its paralog BAZ2B is still undefined. The bromodomains of BAZ2A and BAZ2B have a very similar binding site for their natural ligand, the acetylated lysine side chain. Here, we present an analysis of the binding modes of eight compounds belonging to three distinct chemical classes. For all compounds, the moiety mimicking the natural ligand makes essentially identical interactions in the BAZ2A and BAZ2B bromodomains. In contrast, the rest of the molecule is partially solvent exposed and shows different orientations and interactions in the two bromodomains. Some of these differences could be exploited for designing selective inhibitors within the BAZ2 bromodomain subfamily. | |||
Structural Analysis of Small Molecule Binding to the BAZ2A and BAZ2B Bromodomains.,Dalle Vedove A, Spiliotopoulos D, D'Agostino VG, Marchand JR, Unzue A, Nevado C, Lolli G, Caflisch A ChemMedChem. 2018 May 17. doi: 10.1002/cmdc.201800234. PMID:29770599<ref>PMID:29770599</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
[[Category: | <div class="pdbe-citations 6fgf" style="background-color:#fffaf0;"></div> | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Caflisch, A]] | |||
[[Category: Lolli, G]] | [[Category: Lolli, G]] | ||
[[Category: Spiliotopoulos, D]] | [[Category: Spiliotopoulos, D]] | ||
[[Category: | [[Category: Vedove, A Dalle]] | ||
[[Category: Four helical bundle]] | |||
[[Category: Transcription]] | |||
Revision as of 08:38, 30 May 2018
Crystal Structure of BAZ2A bromodomain in complex with 1-methylpyridinone compound 2Crystal Structure of BAZ2A bromodomain in complex with 1-methylpyridinone compound 2
Structural highlights
Function[BAZ2A_HUMAN] Essential component of the NoRC (nucleolar remodeling complex) complex, a complex that mediates silencing of a fraction of rDNA by recruiting histone-modifying enzymes and DNA methyltransferases, leading to heterochromatin formation and transcriptional silencing. In the complex, it plays a central role by being recruited to rDNA and by targeting chromatin modifying enzymes such as HDAC1, leading to repress RNA polymerase I transcription. Recruited to rDNA via its interaction with TTF1 and its ability to recognize and bind histone H4 acetylated on 'Lys-16' (H4K16ac), leading to deacetylation of H4K5ac, H4K8ac, H4K12ac but not H4K16ac. Specifically binds pRNAs, 150-250 nucleotide RNAs that are complementary in sequence to the rDNA promoter; pRNA-binding is required for heterochromatin formation and rDNA silencing (By similarity). Publication Abstract from PubMedThe bromodomain-containing protein BAZ2A is a validated target in prostate cancer, while the function of its paralog BAZ2B is still undefined. The bromodomains of BAZ2A and BAZ2B have a very similar binding site for their natural ligand, the acetylated lysine side chain. Here, we present an analysis of the binding modes of eight compounds belonging to three distinct chemical classes. For all compounds, the moiety mimicking the natural ligand makes essentially identical interactions in the BAZ2A and BAZ2B bromodomains. In contrast, the rest of the molecule is partially solvent exposed and shows different orientations and interactions in the two bromodomains. Some of these differences could be exploited for designing selective inhibitors within the BAZ2 bromodomain subfamily. Structural Analysis of Small Molecule Binding to the BAZ2A and BAZ2B Bromodomains.,Dalle Vedove A, Spiliotopoulos D, D'Agostino VG, Marchand JR, Unzue A, Nevado C, Lolli G, Caflisch A ChemMedChem. 2018 May 17. doi: 10.1002/cmdc.201800234. PMID:29770599[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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