4zc9 - Revision history

OCA at 12:15, 6 March 2024

OCA — Wed, 06 Mar 2024 12:15:49 GMT

←Older revision		Revision as of 12:15, 6 March 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4zc9]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZC9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZC9 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4zc9]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZC9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZC9 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4MW:2-[(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]-N-(4-{[({2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}oxy)acetyl]amino}butyl)acetamide'>4MW</scene></td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 0.99Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4MW:2-[(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]-N-(4-{[({2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}oxy)acetyl]amino}butyl)acetamide'>4MW</scene></td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4zc9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zc9 OCA], [https://pdbe.org/4zc9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zc9 RCSB], [https://www.ebi.ac.uk/pdbsum/4zc9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zc9 ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4zc9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zc9 OCA], [https://pdbe.org/4zc9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zc9 RCSB], [https://www.ebi.ac.uk/pdbsum/4zc9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zc9 ProSAT]</span></td></tr>
	</table>		</table>
Line 11:		Line 12:
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).		[https://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 ==
-	The development of effective pharmacological inhibitors of multidomain scaffold proteins, notably transcription factors, is a particularly challenging problem. In part, this is because many small-molecule antagonists disrupt the activity of only one domain in the target protein. We devised a chemical strategy that promotes ligand-dependent target protein degradation using as an example the transcriptional coactivator BRD4, a protein critical for cancer cell growth and survival. We appended a competitive antagonist of BET bromodomains to a phthalimide moiety to hijack the cereblon E3 ubiquitin ligase complex. The resultant compound, dBET1, induced highly selective cereblon-dependent BET protein degradation in vitro and in vivo and delayed leukemia progression in mice. A second series of probes resulted in selective degradation of the cytosolic protein FKBP12. This chemical strategy for controlling target protein stability may have implications for therapeutically targeting previously intractable proteins.
-
-	DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation.,Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, Bradner JE Science. 2015 Jun 19;348(6241):1376-81. doi: 10.1126/science.aab1433. Epub 2015, May 21. PMID:25999370<ref>PMID:25999370</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 4zc9" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 07:48, 10 May 2023

OCA — Wed, 10 May 2023 07:48:39 GMT

←Older revision		Revision as of 07:48, 10 May 2023
Line 3:		Line 3:
	<StructureSection load='4zc9' size='340' side='right'caption='[[4zc9]], [[Resolution\|resolution]] 0.99Å' scene=''>		<StructureSection load='4zc9' size='340' side='right'caption='[[4zc9]], [[Resolution\|resolution]] 0.99Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4zc9]] 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=4ZC9 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4ZC9 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4zc9]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZC9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZC9 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4MW:2-[(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]-N-(4-{[({2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}oxy)acetyl]amino}butyl)acetamide'>4MW</scene>~~</td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4MW:2-[(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]-N-(4-{[({2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}oxy)acetyl]amino}butyl)acetamide'>4MW</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'>[https://proteopedia.org/fgij/fg.htm?mol=4zc9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zc9 OCA], [https://pdbe.org/4zc9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zc9 RCSB], [https://www.ebi.ac.uk/pdbsum/4zc9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zc9 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=4zc9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zc9 OCA], [~~http~~://pdbe.org/4zc9 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4zc9 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4zc9 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4zc9 ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[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>	+	[https://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>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).	+	[https://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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 28:		Line 27:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Bradner~~, J E~~]]	+	[[Category: Bradner JE]]
-	[[Category: DeAngelo, S]]	+	[[Category: DeAngelo S]]
-	[[Category: Seo, H S]]	+	[[Category: Seo H-S]]
-	~~[[Category: Bromodomain]]~~	+
-	~~[[Category: Signaling protein-inhibitor complex]]~~	+
-	~~[[Category: Small-molecule complex~~]]	+

OCA at 06:52, 19 June 2019

OCA — Wed, 19 Jun 2019 06:52:07 GMT

←Older revision		Revision as of 06:52, 19 June 2019
Line 1:		Line 1:
		+
	==Crystal Structure of the BRD4a/DB-2-190 complex==		==Crystal Structure of the BRD4a/DB-2-190 complex==
-	<StructureSection load='4zc9' size='340' side='right' caption='[[4zc9]], [[Resolution\|resolution]] 0.99Å' scene=''>	+	<StructureSection load='4zc9' size='340' side='right'caption='[[4zc9]], [[Resolution\|resolution]] 0.99Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4zc9]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZC9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZC9 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4zc9]] 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=4ZC9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZC9 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4MW:2-[(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]-N-(4-{[({2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}oxy)acetyl]amino}butyl)acetamide'>4MW</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4MW:2-[(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]-N-(4-{[({2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}oxy)acetyl]amino}butyl)acetamide'>4MW</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=4zc9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zc9 OCA], [http://pdbe.org/4zc9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zc9 RCSB], [http://www.ebi.ac.uk/pdbsum/4zc9 PDBsum]</span></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=4zc9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zc9 OCA], [http://pdbe.org/4zc9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zc9 RCSB], [http://www.ebi.ac.uk/pdbsum/4zc9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zc9 ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 19:		Line 21:
	</div>		</div>
	<div class="pdbe-citations 4zc9" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4zc9" 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: Bradner, J E]]		[[Category: Bradner, J E]]
	[[Category: DeAngelo, S]]		[[Category: DeAngelo, S]]

OCA at 18:57, 1 December 2015

OCA — Tue, 01 Dec 2015 18:57:35 GMT

←Older revision		Revision as of 18:57, 1 December 2015
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==Crystal Structure of the BRD4a/DB-2-190 complex==
		+	<StructureSection load='4zc9' size='340' side='right' caption='[[4zc9]], [[Resolution\|resolution]] 0.99Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4zc9]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZC9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZC9 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4MW:2-[(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]-N-(4-{[({2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}oxy)acetyl]amino}butyl)acetamide'>4MW</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=4zc9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zc9 OCA], [http://pdbe.org/4zc9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zc9 RCSB], [http://www.ebi.ac.uk/pdbsum/4zc9 PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[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>
		+	== Function ==
		+	[[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 ==
		+	The development of effective pharmacological inhibitors of multidomain scaffold proteins, notably transcription factors, is a particularly challenging problem. In part, this is because many small-molecule antagonists disrupt the activity of only one domain in the target protein. We devised a chemical strategy that promotes ligand-dependent target protein degradation using as an example the transcriptional coactivator BRD4, a protein critical for cancer cell growth and survival. We appended a competitive antagonist of BET bromodomains to a phthalimide moiety to hijack the cereblon E3 ubiquitin ligase complex. The resultant compound, dBET1, induced highly selective cereblon-dependent BET protein degradation in vitro and in vivo and delayed leukemia progression in mice. A second series of probes resulted in selective degradation of the cytosolic protein FKBP12. This chemical strategy for controlling target protein stability may have implications for therapeutically targeting previously intractable proteins.

-	~~The entry 4zc9 is ON HOLD until Paper Publication~~	+	DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation.,Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, Bradner JE Science. 2015 Jun 19;348(6241):1376-81. doi: 10.1126/science.aab1433. Epub 2015, May 21. PMID:25999370<ref>PMID:25999370</ref>

-	~~Authors: Seo~~, H.-S.~~, DeAngelo, S., Bradner, J.E~~.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description: Crystal Structure of the BRD4a~~/DB-2-~~190 complex~~	+	<div class="pdbe-citations 4zc9" style="background-color:#fffaf0;"></div>
-	[[Category: ~~Unreleased Structures~~]]	+	== References ==
-	[[Category: ~~Deangelo~~, S]]	+	<references/>
-	[[Category: Seo, H.-S]]	+	__TOC__
-	[[Category: ~~Bradner, J.E~~]]	+	</StructureSection>
		+	[[Category: Bradner, J E]]
		+	[[Category: DeAngelo, S]]
		+	[[Category: Seo, H S]]
		+	[[Category: Bromodomain]]
		+	[[Category: Signaling protein-inhibitor complex]]
		+	[[Category: Small-molecule complex]]

OCA at 10:45, 3 June 2015

OCA — Wed, 03 Jun 2015 10:45:05 GMT

←Older revision		Revision as of 10:45, 3 June 2015
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4zc9 is ON HOLD	+	The entry 4zc9 is ON HOLD until Paper Publication

	Authors: Seo, H.-S., DeAngelo, S., Bradner, J.E.		Authors: Seo, H.-S., DeAngelo, S., Bradner, J.E.

OCA: Protected "4zc9" [edit=sysop:move=sysop]

OCA — Wed, 22 Apr 2015 11:42:20 GMT

Protected "4zc9" [edit=sysop:move=sysop]

←Older revision

Revision as of 11:42, 22 April 2015

OCA: New page: '''Unreleased structure''' The entry 4zc9 is ON HOLD Authors: Seo, H.-S., DeAngelo, S., Bradner, J.E. Description: Crystal Structure of the BRD4a/DB-2-190 complex [[Category: Unrelease...

OCA — Wed, 22 Apr 2015 11:42:19 GMT

New page: '''Unreleased structure''' The entry 4zc9 is ON HOLD Authors: Seo, H.-S., DeAngelo, S., Bradner, J.E. Description: Crystal Structure of the BRD4a/DB-2-190 complex [[Category: Unrelease...

New page

'''Unreleased structure'''

The entry 4zc9 is ON HOLD

Authors: Seo, H.-S., DeAngelo, S., Bradner, J.E.

Description: Crystal Structure of the BRD4a/DB-2-190 complex
[[Category: Unreleased Structures]]
[[Category: Deangelo, S]]
[[Category: Seo, H.-S]]
[[Category: Bradner, J.E]]