4ir3: Difference between revisions
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==Crystal Structure of the bromodomain of human BAZ2B in complex with 1-[7-amino-1-(pyrimidin-2-yl)indolizin-3-yl]ethanone (GSK2833282A)== | |||
<StructureSection load='4ir3' size='340' side='right'caption='[[4ir3]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4ir3]] is a 1 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=4IR3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IR3 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1FK:1-[7-AMINO-1-(PYRIMIDIN-2-YL)INDOLIZIN-3-YL]ETHANONE'>1FK</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=4ir3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ir3 OCA], [https://pdbe.org/4ir3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ir3 RCSB], [https://www.ebi.ac.uk/pdbsum/4ir3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ir3 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/BAZ2B_HUMAN BAZ2B_HUMAN] May play a role in transcriptional regulation interacting with ISWI. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Bromodomains are acetyl-lysine specific protein interaction domains that have recently emerged as a new target class for the development of inhibitors that modulate gene transcription. The two closely related bromodomain containing proteins BAZ2A and BAZ2B constitute the central scaffolding protein of the nucleolar remodeling complex (NoRC) that regulates the expression of noncoding RNAs. However, BAZ2 bromodomains have low predicted druggability and so far no selective inhibitors have been published. Here we report the development of GSK2801, a potent, selective and cell active acetyl-lysine competitive inhibitor of BAZ2A and BAZ2B bromodomains as well as the inactive control compound GSK8573. GSK2801 binds to BAZ2 bromodomains with dissociation constants (KD) of 136 and 257 nM for BAZ2B and BAZ2A, respectively. Crystal structures demonstrated a canonical acetyl-lysine competitive binding mode. Cellular activity was demonstrated using fluorescent recovery after photobleaching (FRAP) monitoring displacement of GFP-BAZ2A from acetylated chromatin. A pharmacokinetic study in mice showed that GSK2801 had reasonable in vivo exposure after oral dosing, with modest clearance and reasonable plasma stability. Thus, GSK2801 represents a versatile tool compound for cellular and in vivo studies to understand the role of BAZ2 bromodomains in chromatin biology. | |||
Discovery and Characterization of GSK2801, a Selective Chemical Probe for the Bromodomains BAZ2A and BAZ2B.,Chen P, Chaikuad A, Bamborough P, Bantscheff M, Bountra C, Chung CW, Fedorov O, Grandi P, Jung D, Lesniak R, Lindon M, Muller S, Philpott M, Prinjha R, Rogers C, Selenski C, Tallant C, Werner T, Willson TM, Knapp S, Drewry DH J Med Chem. 2015 Apr 6. PMID:25799074<ref>PMID:25799074</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4ir3" style="background-color:#fffaf0;"></div> | |||
== | ==See Also== | ||
[[ | *[[Bromodomain adjacent to zinc finger 3D structures|Bromodomain adjacent to zinc finger 3D structures]] | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Arrowsmith | [[Category: Large Structures]] | ||
[[Category: Bountra | [[Category: Arrowsmith CH]] | ||
[[Category: Chaikuad | [[Category: Bountra C]] | ||
[[Category: Chen | [[Category: Chaikuad A]] | ||
[[Category: Chung | [[Category: Chen P]] | ||
[[Category: Chung CW]] | |||
[[Category: Drewry | [[Category: Drewry D]] | ||
[[Category: Edwards | [[Category: Edwards AM]] | ||
[[Category: Fedorov | [[Category: Fedorov O]] | ||
[[Category: Felletar | [[Category: Felletar I]] | ||
[[Category: Filippakopoulos | [[Category: Filippakopoulos P]] | ||
[[Category: Knapp | [[Category: Knapp S]] | ||
[[Category: Krojer | [[Category: Krojer T]] | ||
[[Category: | [[Category: Von Delft F]] | ||
Latest revision as of 18:29, 20 September 2023
Crystal Structure of the bromodomain of human BAZ2B in complex with 1-[7-amino-1-(pyrimidin-2-yl)indolizin-3-yl]ethanone (GSK2833282A)Crystal Structure of the bromodomain of human BAZ2B in complex with 1-[7-amino-1-(pyrimidin-2-yl)indolizin-3-yl]ethanone (GSK2833282A)
Structural highlights
FunctionBAZ2B_HUMAN May play a role in transcriptional regulation interacting with ISWI. Publication Abstract from PubMedBromodomains are acetyl-lysine specific protein interaction domains that have recently emerged as a new target class for the development of inhibitors that modulate gene transcription. The two closely related bromodomain containing proteins BAZ2A and BAZ2B constitute the central scaffolding protein of the nucleolar remodeling complex (NoRC) that regulates the expression of noncoding RNAs. However, BAZ2 bromodomains have low predicted druggability and so far no selective inhibitors have been published. Here we report the development of GSK2801, a potent, selective and cell active acetyl-lysine competitive inhibitor of BAZ2A and BAZ2B bromodomains as well as the inactive control compound GSK8573. GSK2801 binds to BAZ2 bromodomains with dissociation constants (KD) of 136 and 257 nM for BAZ2B and BAZ2A, respectively. Crystal structures demonstrated a canonical acetyl-lysine competitive binding mode. Cellular activity was demonstrated using fluorescent recovery after photobleaching (FRAP) monitoring displacement of GFP-BAZ2A from acetylated chromatin. A pharmacokinetic study in mice showed that GSK2801 had reasonable in vivo exposure after oral dosing, with modest clearance and reasonable plasma stability. Thus, GSK2801 represents a versatile tool compound for cellular and in vivo studies to understand the role of BAZ2 bromodomains in chromatin biology. Discovery and Characterization of GSK2801, a Selective Chemical Probe for the Bromodomains BAZ2A and BAZ2B.,Chen P, Chaikuad A, Bamborough P, Bantscheff M, Bountra C, Chung CW, Fedorov O, Grandi P, Jung D, Lesniak R, Lindon M, Muller S, Philpott M, Prinjha R, Rogers C, Selenski C, Tallant C, Werner T, Willson TM, Knapp S, Drewry DH J Med Chem. 2015 Apr 6. PMID:25799074[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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