6yb4
From Proteopedia
(Difference between revisions)
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==Crystal structure of human ATAD2 bromodomain in complex with N-(4-bromo-3-(3-methylpyrrolidin-1-yl)sulfonyl)phenyl)-2-(-4-cyclopropyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetamide== | ==Crystal structure of human ATAD2 bromodomain in complex with N-(4-bromo-3-(3-methylpyrrolidin-1-yl)sulfonyl)phenyl)-2-(-4-cyclopropyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetamide== | ||
| - | <StructureSection load='6yb4' size='340' side='right'caption='[[6yb4]]' scene=''> | + | <StructureSection load='6yb4' size='340' side='right'caption='[[6yb4]], [[Resolution|resolution]] 1.85Å' 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=6YB4 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6YB4 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6yb4]] 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=6YB4 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6YB4 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=6yb4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yb4 OCA], [http://pdbe.org/6yb4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6yb4 RCSB], [http://www.ebi.ac.uk/pdbsum/6yb4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6yb4 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=OJH:~{N}-[4-bromanyl-3-[(3~{S})-3-methylpyrrolidin-1-yl]sulfonyl-phenyl]-2-[(4~{R})-4-cyclopropyl-4-methyl-2,5-bis(oxidanylidene)imidazolidin-1-yl]ethanamide'>OJH</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ATAD2, L16, PRO2000 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Adenosinetriphosphatase Adenosinetriphosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.1.3 3.6.1.3] </span></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=6yb4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yb4 OCA], [http://pdbe.org/6yb4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6yb4 RCSB], [http://www.ebi.ac.uk/pdbsum/6yb4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6yb4 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/ATAD2_HUMAN ATAD2_HUMAN]] May be a transcriptional coactivator of the nuclear receptor ESR1 required to induce the expression of a subset of estradiol target genes, such as CCND1, MYC and E2F1. May play a role in the recruitment or occupancy of CREBBP at some ESR1 target gene promoters. May be required for histone hyperacetylation. Involved in the estrogen-induced cell proliferation and cell cycle progression of breast cancer cells.<ref>PMID:17998543</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Most bromodomain inhibitors mimic the interactions of the natural acetylated lysine (KAc) histone substrate through key interactions with conserved asparagine and tyrosine residues within the binding pocket. Herein we report the optimisation of a series of phenyl sulfonamides which exhibit a novel mode of binding to non-Bromodomain and Extra Terminal Domain (non-BET) bromodomains through displacement of a normally conserved network of four water molecules. Starting from an initial hit molecule we report its divergent optimisation towards the ATPase family AAA domain containing 2 (ATAD2) and Cats Eye Syndrome Chromosome Region, Candidate 2 (CECR2) domains. This work concludes with the identification of (R)-55 (GSK232), a highly selective, cellularly penetrant CECR2 inhibitor with excellent physicochemical properties. | ||
| + | |||
| + | The Optimisation of Potent ATAD2 and CECR2 Bromodomain Inhibitors with an Atypical Binding Mode.,Lucas S, Atkinson SJ, Bamborough P, Barnett HA, Chung CW, Gordon LJ, Mitchell DJ, Phillipou A, Prinjha RK, Sheppard RJ, Tomkinson NCO, Watson RJ, Demont EH J Med Chem. 2020 Apr 22. doi: 10.1021/acs.jmedchem.0c00021. PMID:32321240<ref>PMID:32321240</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6yb4" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Adenosinetriphosphatase]] | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Chung C]] | + | [[Category: Chung, C]] |
| + | [[Category: Atad2]] | ||
| + | [[Category: Atpase family aaa domain-containing protein 2]] | ||
| + | [[Category: Bromodomain]] | ||
| + | [[Category: Epigenetic]] | ||
| + | [[Category: Inhibitor]] | ||
| + | [[Category: Transcription]] | ||
Current revision
Crystal structure of human ATAD2 bromodomain in complex with N-(4-bromo-3-(3-methylpyrrolidin-1-yl)sulfonyl)phenyl)-2-(-4-cyclopropyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetamide
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