6fsy - Revision history

OCA at 07:52, 24 April 2019

OCA — Wed, 24 Apr 2019 07:52:57 GMT

←Older revision		Revision as of 07:52, 24 April 2019
Line 1:		Line 1:

	==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='6fsy' size='340' side='right' caption='[[6fsy]], [[Resolution\|resolution]] 1.34Å' scene=''>	+	<StructureSection load='6fsy' size='340' side='right'caption='[[6fsy]], [[Resolution\|resolution]] 1.34Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6fsy]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FSY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FSY FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6fsy]] 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=6FSY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FSY FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=E5Q:3-(3,5-dimethyl-1,2-oxazol-4-yl)-5-[(~{R})-oxidanyl(pyridin-3-yl)methyl]phenol'>E5Q</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=E5Q:3-(3,5-dimethyl-1,2-oxazol-4-yl)-5-[(~{R})-oxidanyl(pyridin-3-yl)methyl]phenol'>E5Q</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=6fsy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fsy OCA], [http://pdbe.org/6fsy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fsy RCSB], [http://www.ebi.ac.uk/pdbsum/6fsy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fsy 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=6fsy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fsy OCA], [http://pdbe.org/6fsy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fsy RCSB], [http://www.ebi.ac.uk/pdbsum/6fsy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fsy ProSAT]</span></td></tr>
	</table>		</table>
Line 11:		Line 12:
	== 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 6fsy" 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]]

OCA at 05:52, 18 April 2018

OCA — Wed, 18 Apr 2018 05:52:15 GMT

←Older revision		Revision as of 05:52, 18 April 2018
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6fsy ~~is ON HOLD~~	+	==Crystal Structure of the first bromodomain of human BRD4 in complex with a 3,5-dimethylisoxazol ligand==
-		+	<StructureSection load='6fsy' size='340' side='right' caption='[[6fsy]], [[Resolution\|resolution]] 1.34Å' scene=''>
-	~~Authors~~: ~~Filippakopoulos, P~~.~~, Picaud, S~~.~~, Conway, S~~.J.~~, Pike, A~~.C.W., ~~Krojer~~, T., ~~von Delft~~, F., ~~Arrowsmith, C~~.H., ~~Edwards~~, A.M., ~~Bountra, C~~., ~~Structural Genomics Consortium (SGC)~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[6fsy]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FSY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FSY FirstGlance]. <br>
-	~~Description~~: ~~Crystal Structure of the first bromodomain of human~~ BRD4 in ~~complex with~~ a 3,5-~~dimethylisoxazol ligand~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=E5Q:3-(3,5-dimethyl-1,2-oxazol-4-yl)-5-[(~{R})-oxidanyl(pyridin-3-yl)methyl]phenol'>E5Q</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
-	[[~~Category~~: ~~Unreleased Structures~~]]	+	<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=6fsy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fsy OCA], [http://pdbe.org/6fsy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fsy RCSB], [http://www.ebi.ac.uk/pdbsum/6fsy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fsy ProSAT]</span></td></tr>
-	[[Category: ~~Pike~~, A.C.W]]	+	</table>
-	[[Category: ~~Arrowsmith~~, C.H]]	+	== Disease ==
-	[[Category: ~~Von Delft~~, F]]	+	[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.<ref>PMID:12543779</ref> <ref>PMID:11733348</ref>
-	[[Category: ~~Picaud~~, S]]	+	== Function ==
-	[[Category: ~~Conway~~, ~~S.J~~]]	+	[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Arrowsmith, C H]]
		+	[[Category: Bountra, C]]
		+	[[Category: Conway, S J]]
		+	[[Category: Delft, F von]]
		+	[[Category: Edwards, A M]]
	[[Category: Filippakopoulos, P]]		[[Category: Filippakopoulos, P]]
-	[[Category: Edwards, A.M]]
-	[[Category: Structural Genomics Consortium (Sgc)]]
	[[Category: Krojer, T]]		[[Category: Krojer, T]]
-	[[Category: ~~Bountra~~, C]]	+	[[Category: Picaud, S]]
		+	[[Category: Pike, A C.W]]
		+	[[Category: Structural genomic]]
		+	[[Category: Bromodomain]]
		+	[[Category: Isoxazole]]
		+	[[Category: Ligand]]
		+	[[Category: Sgc]]
		+	[[Category: Transcription]]

OCA: Protected "6fsy" [edit=sysop:move=sysop]

OCA — Wed, 28 Feb 2018 05:13:33 GMT

Protected "6fsy" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:13, 28 February 2018

OCA: New page: '''Unreleased structure''' The entry 6fsy is ON HOLD Authors: Filippakopoulos, P., Picaud, S., Conway, S.J., Pike, A.C.W., Krojer, T., von Delft, F., Arrowsmith, C.H., Edwards, A.M., Bo...

OCA — Wed, 28 Feb 2018 05:13:32 GMT

New page: '''Unreleased structure''' The entry 6fsy is ON HOLD Authors: Filippakopoulos, P., Picaud, S., Conway, S.J., Pike, A.C.W., Krojer, T., von Delft, F., Arrowsmith, C.H., Edwards, A.M., Bo...

New page

'''Unreleased structure'''

The entry 6fsy is ON HOLD

Authors: Filippakopoulos, P., Picaud, S., Conway, S.J., Pike, A.C.W., Krojer, T., von Delft, F., Arrowsmith, C.H., Edwards, A.M., Bountra, C., Structural Genomics Consortium (SGC)

Description: Crystal Structure of the first bromodomain of human BRD4 in complex with a 3,5-dimethylisoxazol ligand
[[Category: Unreleased Structures]]
[[Category: Pike, A.C.W]]
[[Category: Arrowsmith, C.H]]
[[Category: Von Delft, F]]
[[Category: Picaud, S]]
[[Category: Conway, S.J]]
[[Category: Filippakopoulos, P]]
[[Category: Edwards, A.M]]
[[Category: Structural Genomics Consortium (Sgc)]]
[[Category: Krojer, T]]
[[Category: Bountra, C]]