4z6i: Difference between revisions
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''' | ==Crystal structure of BRD9 bromodomain in complex with a substituted valerolactam quinolone ligand== | ||
<StructureSection load='4z6i' size='340' side='right' caption='[[4z6i]], [[Resolution|resolution]] 1.95Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4z6i]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Z6I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Z6I FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4L3:TERT-BUTYL+[(2R,3S)-1-(1,4-DIMETHYL-2-OXO-1,2-DIHYDROQUINOLIN-7-YL)-6-OXO-2-PHENYLPIPERIDIN-3-YL]CARBAMATE'>4L3</scene></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=4z6i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4z6i OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4z6i RCSB], [http://www.ebi.ac.uk/pdbsum/4z6i PDBsum]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/BRD9_HUMAN BRD9_HUMAN]] May play a role in chromatin remodeling and regulation of transcription. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The bromodomain-containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin-remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone-fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure-based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity-building nitro-Mannich/lactamization cascade processes allowed for early structure-activity relationship studies whereas an enantioselective organocatalytic nitro-Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones in vitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro-inflammatory cytokine secretion. | |||
LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor.,Clark PG, Vieira LC, Tallant C, Fedorov O, Singleton DC, Rogers CM, Monteiro OP, Bennett JM, Baronio R, Muller S, Daniels DL, Mendez J, Knapp S, Brennan PE, Dixon DJ Angew Chem Int Ed Engl. 2015 May 18;54(21):6217-21. doi: 10.1002/anie.201501394. , Epub 2015 Apr 13. PMID:25864491<ref>PMID:25864491</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
</StructureSection> | |||
[[Category: Arrowsmith, C H]] | |||
[[Category: Bountra, C]] | |||
[[Category: Brennan, P E]] | |||
[[Category: Clark, P G.K]] | |||
[[Category: Delft, F von]] | |||
[[Category: Dixon, D J]] | |||
[[Category: Edwards, A M]] | |||
[[Category: Fedorov, O]] | [[Category: Fedorov, O]] | ||
[[Category: Knapp, S]] | [[Category: Knapp, S]] | ||
[[Category: Krojer, T]] | [[Category: Krojer, T]] | ||
[[Category: | [[Category: Newman, J A]] | ||
[[Category: Nunez-Alonso, G]] | |||
[[Category: Picaud, S]] | |||
[[Category: Structural genomic]] | |||
[[Category: | |||
[[Category: | |||
[[Category: | |||
[[Category: Tallant, C]] | [[Category: Tallant, C]] | ||
[[Category: Vieira, L C.C]] | |||
[[Category: Bromodomain]] | |||
[[Category: Chromatin regulator]] | |||
[[Category: Lysine-acetylated histone binding]] | |||
[[Category: Sgc]] | |||
[[Category: Transcription]] | |||
Revision as of 15:11, 20 May 2015
Crystal structure of BRD9 bromodomain in complex with a substituted valerolactam quinolone ligandCrystal structure of BRD9 bromodomain in complex with a substituted valerolactam quinolone ligand
Structural highlights
Function[BRD9_HUMAN] May play a role in chromatin remodeling and regulation of transcription. Publication Abstract from PubMedThe bromodomain-containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin-remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone-fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure-based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity-building nitro-Mannich/lactamization cascade processes allowed for early structure-activity relationship studies whereas an enantioselective organocatalytic nitro-Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones in vitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro-inflammatory cytokine secretion. LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor.,Clark PG, Vieira LC, Tallant C, Fedorov O, Singleton DC, Rogers CM, Monteiro OP, Bennett JM, Baronio R, Muller S, Daniels DL, Mendez J, Knapp S, Brennan PE, Dixon DJ Angew Chem Int Ed Engl. 2015 May 18;54(21):6217-21. doi: 10.1002/anie.201501394. , Epub 2015 Apr 13. PMID:25864491[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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