6ft4: Difference between revisions
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==Crystal Structure of the first bromodomain of human BRD4 in complex with a 3,5-dimethylisoxazol ligand== | ==Crystal Structure of the first bromodomain of human BRD4 in complex with a 3,5-dimethylisoxazol ligand== | ||
<StructureSection load='6ft4' size='340' side='right' caption='[[6ft4]], [[Resolution|resolution]] 1.34Å' scene=''> | <StructureSection load='6ft4' size='340' side='right'caption='[[6ft4]], [[Resolution|resolution]] 1.34Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6ft4]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FT4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FT4 FirstGlance]. <br> | <table><tr><td colspan='2'>[[6ft4]] 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=6FT4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FT4 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=E5W:3-[[4,4-bis(fluoranyl)piperidin-1-yl]methyl]-5-(3,5-dimethyl-1,2-oxazol-4-yl)phenol'>E5W</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=E5W:3-[[4,4-bis(fluoranyl)piperidin-1-yl]methyl]-5-(3,5-dimethyl-1,2-oxazol-4-yl)phenol'>E5W</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BRD4, HUNK1 ([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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ft4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ft4 OCA], [http://pdbe.org/6ft4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ft4 RCSB], [http://www.ebi.ac.uk/pdbsum/6ft4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ft4 ProSAT]</span></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=6ft4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ft4 OCA], [http://pdbe.org/6ft4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ft4 RCSB], [http://www.ebi.ac.uk/pdbsum/6ft4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ft4 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). | [[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Ligands for the bromodomain and extra-terminal domain (BET) family of bromodomains have shown promise as useful therapeutic agents for treating a range of cancers and inflammation. Here we report that our previously developed 3,5-dimethylisoxazole-based BET bromodomain ligand (OXFBD02) inhibits interactions of BRD4(1) with the RelA subunit of NF-kappaB, in addition to histone H4. This ligand shows a promising profile in a screen of the NCI-60 panel but was rapidly metabolised (t(1/2)=39.8min). Structure-guided optimisation of compound properties led to the development of the 3-pyridyl-derived OXFBD04. Molecular dynamics simulations assisted our understanding of the role played by an internal hydrogen bond in altering the affinity of this series of molecules for BRD4(1). OXFBD04 shows improved BRD4(1) affinity (IC50=166nM), optimised physicochemical properties (LE=0.43; LLE=5.74; SFI=5.96), and greater metabolic stability (t(1/2)=388min). | |||
BET bromodomain ligands: Probing the WPF shelf to improve BRD4 bromodomain affinity and metabolic stability.,Jennings LE, Schiedel M, Hewings DS, Picaud S, Laurin CMC, Bruno PA, Bluck JP, Scorah AR, See L, Reynolds JK, Moroglu M, Mistry IN, Hicks A, Guzanov P, Clayton J, Evans CNG, Stazi G, Biggin PC, Mapp AK, Hammond EM, Humphreys PG, Filippakopoulos P, Conway SJ Bioorg Med Chem. 2018 Jul 15;26(11):2937-2957. doi: 10.1016/j.bmc.2018.05.003., Epub 2018 May 15. PMID:29776834<ref>PMID:29776834</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6ft4" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Arrowsmith, C H]] | [[Category: Arrowsmith, C H]] | ||
[[Category: Bountra, C]] | [[Category: Bountra, C]] | ||