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==C-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH 1-benzyl-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide== | ==C-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH 1-benzyl-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide== | ||
<StructureSection load='6zb0' size='340' side='right'caption='[[6zb0]]' scene=''> | <StructureSection load='6zb0' size='340' side='right'caption='[[6zb0]], [[Resolution|resolution]] 1.61Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZB0 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZB0 FirstGlance]. <br> | <table><tr><td colspan='2'>[[6zb0]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZB0 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZB0 FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6zb0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zb0 OCA], [http://pdbe.org/6zb0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6zb0 RCSB], [http://www.ebi.ac.uk/pdbsum/6zb0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6zb0 ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=QCW:~{N}-methyl-2-oxidanylidene-1-(phenylmethyl)pyridine-3-carboxamide'>QCW</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BRD2, KIAA9001, RING3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6zb0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zb0 OCA], [http://pdbe.org/6zb0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6zb0 RCSB], [http://www.ebi.ac.uk/pdbsum/6zb0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6zb0 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[http://www.uniprot.org/uniprot/BRD2_HUMAN BRD2_HUMAN]] May play a role in spermatogenesis or folliculogenesis (By similarity). Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling. Regulates transcription of the CCND1 gene. Plays a role in nucleosome assembly.<ref>PMID:18406326</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The profound efficacy, yet associated toxicity of pan-BET inhibitors is well documented. The possibility of an ameliorated safety profile driven by significantly selective (>100 fold) inhibition of a sub-set of the 8 bromodomains is enticing, but challenging given the close homology. Herein, we describe the X-ray crystal structure-directed optimisation of a novel weak fragment ligand with a pan-second bromodomain (BD2) bias, to potent and highly BD2 selective inhibitors. A template hopping approach, enabled by our parallel research into an orthogonal template (15, GSK046) was the basis for the high selectivity observed. This culminated in two tool molecules 20 (GSK620) and 56 (GSK549) which showed an anti-inflammatory phenotype in human whole blood, confirming their cellular target engagement. Excellent broad selectivity, developability and in vivo oral pharmacokinetics characterize these tools, which we hope will be of broad utility to the field of epigenetics research. | |||
The Optimisation of a Novel, Weak Bromo and Extra Terminal Domain (BET) Bromodomain Fragment Ligand to a Potent and Selective Second Bromodomain (BD2) Inhibitor.,Seal JT, Atkinson SJ, Aylott H, Bamborough P, Chung CW, Copley RCB, Gordon LJ, Grandi P, Gray JRJ, Harrison LA, Hayhow TG, Lindon M, Messenger C, Michon AM, Mitchell DJ, Preston A, Prinjha RK, Rioja I, Taylor S, Wall ID, Watson RJ, Woolven JM, Demont EH J Med Chem. 2020 Jul 23. doi: 10.1021/acs.jmedchem.0c00796. PMID:32702236<ref>PMID:32702236</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6zb0" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Chung C]] | [[Category: Chung, C]] | ||
[[Category: Antagonist]] | |||
[[Category: Brd2]] | |||
[[Category: Bromodomain]] | |||
[[Category: Bromodomain containing protein 2]] | |||
[[Category: Epigenetic reader]] | |||
[[Category: Histone]] | |||
[[Category: Inhibitor]] | |||
[[Category: Transcription]] | |||
Revision as of 14:35, 23 September 2020
C-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH 1-benzyl-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamideC-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH 1-benzyl-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide
Structural highlights
Function[BRD2_HUMAN] May play a role in spermatogenesis or folliculogenesis (By similarity). Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling. Regulates transcription of the CCND1 gene. Plays a role in nucleosome assembly.[1] Publication Abstract from PubMedThe profound efficacy, yet associated toxicity of pan-BET inhibitors is well documented. The possibility of an ameliorated safety profile driven by significantly selective (>100 fold) inhibition of a sub-set of the 8 bromodomains is enticing, but challenging given the close homology. Herein, we describe the X-ray crystal structure-directed optimisation of a novel weak fragment ligand with a pan-second bromodomain (BD2) bias, to potent and highly BD2 selective inhibitors. A template hopping approach, enabled by our parallel research into an orthogonal template (15, GSK046) was the basis for the high selectivity observed. This culminated in two tool molecules 20 (GSK620) and 56 (GSK549) which showed an anti-inflammatory phenotype in human whole blood, confirming their cellular target engagement. Excellent broad selectivity, developability and in vivo oral pharmacokinetics characterize these tools, which we hope will be of broad utility to the field of epigenetics research. The Optimisation of a Novel, Weak Bromo and Extra Terminal Domain (BET) Bromodomain Fragment Ligand to a Potent and Selective Second Bromodomain (BD2) Inhibitor.,Seal JT, Atkinson SJ, Aylott H, Bamborough P, Chung CW, Copley RCB, Gordon LJ, Grandi P, Gray JRJ, Harrison LA, Hayhow TG, Lindon M, Messenger C, Michon AM, Mitchell DJ, Preston A, Prinjha RK, Rioja I, Taylor S, Wall ID, Watson RJ, Woolven JM, Demont EH J Med Chem. 2020 Jul 23. doi: 10.1021/acs.jmedchem.0c00796. PMID:32702236[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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