5j7g - Revision history

OCA at 10:52, 6 September 2023

OCA — Wed, 06 Sep 2023 10:52:13 GMT

←Older revision		Revision as of 10:52, 6 September 2023
Line 1:		Line 1:

	==Structure of MDM2 with low molecular weight inhibitor with aliphatic linker.==		==Structure of MDM2 with low molecular weight inhibitor with aliphatic linker.==
-	<StructureSection load='5j7g' size='340' side='right' caption='[[5j7g]], [[Resolution\|resolution]] 1.85Å' scene=''>	+	<StructureSection load='5j7g' size='340' side='right'caption='[[5j7g]], [[Resolution\|resolution]] 1.85Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5j7g]] is a 4 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=5J7G OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5J7G FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5j7g]] is a 4 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=5J7G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5J7G FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6GG:4-({6-[(6-CHLORO-3-{1-[(4-CHLOROPHENYL)METHYL]-4-(4-FLUOROPHENYL)-1H-IMIDAZOL-5-YL}-1H-INDOLE-2-CARBONYL)OXY]HEXYL}AMINO)-4-OXOBUTANOIC+ACID'>6GG</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]] 1.85Å</td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">MDM2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])~~</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6GG:4-({6-[(6-CHLORO-3-{1-[(4-CHLOROPHENYL)METHYL]-4-(4-FLUOROPHENYL)-1H-IMIDAZOL-5-YL}-1H-INDOLE-2-CARBONYL)OXY]HEXYL}AMINO)-4-OXOBUTANOIC+ACID'>6GG</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=5j7g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j7g OCA], [~~http~~://pdbe.org/5j7g PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5j7g RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5j7g PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5j7g 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=5j7g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j7g OCA], [https://pdbe.org/5j7g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5j7g RCSB], [https://www.ebi.ac.uk/pdbsum/5j7g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5j7g ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/MDM2_HUMAN MDM2_HUMAN]] Note=Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding.	+	[https://www.uniprot.org/uniprot/MDM2_HUMAN MDM2_HUMAN] Note=Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding.
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/MDM2_HUMAN MDM2_HUMAN]] E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as an ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and promotes it to proteasomal degradation.<ref>PMID:12821780</ref> <ref>PMID:15053880</ref> <ref>PMID:15195100</ref> <ref>PMID:16337594</ref> <ref>PMID:15632057</ref> <ref>PMID:17290220</ref> <ref>PMID:19098711</ref> <ref>PMID:19219073</ref> <ref>PMID:19965871</ref> <ref>PMID:20858735</ref> <ref>PMID:20173098</ref>	+	[https://www.uniprot.org/uniprot/MDM2_HUMAN MDM2_HUMAN] E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as an ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and promotes it to proteasomal degradation.<ref>PMID:12821780</ref> <ref>PMID:15053880</ref> <ref>PMID:15195100</ref> <ref>PMID:16337594</ref> <ref>PMID:15632057</ref> <ref>PMID:17290220</ref> <ref>PMID:19098711</ref> <ref>PMID:19219073</ref> <ref>PMID:19965871</ref> <ref>PMID:20858735</ref> <ref>PMID:20173098</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 21:		Line 21:
	</div>		</div>
	<div class="pdbe-citations 5j7g" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5j7g" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[MDM2 3D structures\|MDM2 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: Dubin, G]]	+	[[Category: Large Structures]]
-	[[Category: Guzik, K]]	+	[[Category: Dubin G]]
-	[[Category: Holak~~, T A~~]]	+	[[Category: Guzik K]]
-	[[Category: Kubica, K]]	+	[[Category: Holak TA]]
-	[[Category: Twarda-Clapa, A]]	+	[[Category: Kubica K]]
-	~~[[Category: Cancer]]~~	+	[[Category: Twarda-Clapa A]]
-	~~[[Category: Inhibitor]]~~	+
-	~~[[Category: Ligase]]~~	+
-	~~[[Category: Mdm2]]~~	+
-	~~[[Category: Mdmx]]~~	+
-	~~[[Category: P53]]~~	+
-	~~[[Category: Protein-protein interaction~~]]	+

OCA at 06:53, 31 January 2018

OCA — Wed, 31 Jan 2018 06:53:33 GMT

←Older revision		Revision as of 06:53, 31 January 2018
Line 3:		Line 3:
	<StructureSection load='5j7g' size='340' side='right' caption='[[5j7g]], [[Resolution\|resolution]] 1.85Å' scene=''>		<StructureSection load='5j7g' size='340' side='right' caption='[[5j7g]], [[Resolution\|resolution]] 1.85Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5j7g]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J7G OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5J7G FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5j7g]] is a 4 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=5J7G OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5J7G FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6GG:4-({6-[(6-CHLORO-3-{1-[(4-CHLOROPHENYL)METHYL]-4-(4-FLUOROPHENYL)-1H-IMIDAZOL-5-YL}-1H-INDOLE-2-CARBONYL)OXY]HEXYL}AMINO)-4-OXOBUTANOIC+ACID'>6GG</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6GG:4-({6-[(6-CHLORO-3-{1-[(4-CHLOROPHENYL)METHYL]-4-(4-FLUOROPHENYL)-1H-IMIDAZOL-5-YL}-1H-INDOLE-2-CARBONYL)OXY]HEXYL}AMINO)-4-OXOBUTANOIC+ACID'>6GG</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">MDM2 ([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=5j7g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j7g OCA], [http://pdbe.org/5j7g PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j7g RCSB], [http://www.ebi.ac.uk/pdbsum/5j7g PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j7g 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=5j7g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j7g OCA], [http://pdbe.org/5j7g PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j7g RCSB], [http://www.ebi.ac.uk/pdbsum/5j7g PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j7g ProSAT]</span></td></tr>
	</table>		</table>
Line 24:		Line 25:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Dubin, G]]		[[Category: Dubin, G]]
	[[Category: Guzik, K]]		[[Category: Guzik, K]]

OCA at 11:14, 16 November 2017

OCA — Thu, 16 Nov 2017 11:14:51 GMT

←Older revision		Revision as of 11:14, 16 November 2017
Line 20:		Line 20:
	</div>		</div>
	<div class="pdbe-citations 5j7g" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5j7g" style="background-color:#fffaf0;"></div>
-
-	==See Also==
-	*[[MDM2\|MDM2]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 10:08, 3 August 2017

OCA — Thu, 03 Aug 2017 10:08:48 GMT

←Older revision		Revision as of 10:08, 3 August 2017
Line 20:		Line 20:
	</div>		</div>
	<div class="pdbe-citations 5j7g" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5j7g" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[MDM2\|MDM2]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 15:40, 17 May 2017

OCA — Wed, 17 May 2017 15:40:14 GMT

←Older revision		Revision as of 15:40, 17 May 2017
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5j7g is ~~ON HOLD~~ ~~until Jul 06 2018~~	+	==Structure of MDM2 with low molecular weight inhibitor with aliphatic linker.==
		+	<StructureSection load='5j7g' size='340' side='right' caption='[[5j7g]], [[Resolution\|resolution]] 1.85Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5j7g]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J7G OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5J7G FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6GG:4-({6-[(6-CHLORO-3-{1-[(4-CHLOROPHENYL)METHYL]-4-(4-FLUOROPHENYL)-1H-IMIDAZOL-5-YL}-1H-INDOLE-2-CARBONYL)OXY]HEXYL}AMINO)-4-OXOBUTANOIC+ACID'>6GG</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=5j7g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j7g OCA], [http://pdbe.org/5j7g PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j7g RCSB], [http://www.ebi.ac.uk/pdbsum/5j7g PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j7g ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/MDM2_HUMAN MDM2_HUMAN]] Note=Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding.
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/MDM2_HUMAN MDM2_HUMAN]] E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as an ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and promotes it to proteasomal degradation.<ref>PMID:12821780</ref> <ref>PMID:15053880</ref> <ref>PMID:15195100</ref> <ref>PMID:16337594</ref> <ref>PMID:15632057</ref> <ref>PMID:17290220</ref> <ref>PMID:19098711</ref> <ref>PMID:19219073</ref> <ref>PMID:19965871</ref> <ref>PMID:20858735</ref> <ref>PMID:20173098</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The tumor suppressor protein p53, the "guardian of the genome", is inactivated in nearly all cancer types by mutations in the TP53 gene or by overexpression of its negative regulators, oncoproteins MDM2/MDMX. Recovery of p53 function by disrupting the p53-MDM2/MDMX interaction using small-molecule antagonists could provide an efficient nongenotoxic anticancer therapy. Here we present the syntheses, activities, and crystal structures of the p53-MDM2/MDMX inhibitors based on the 1,4,5-trisubstituted imidazole scaffold which are appended with aliphatic linkers that enable coupling to bioactive carriers. The compounds have favorable properties at both biochemical and cellular levels. The most effective compound 19 is a tight binder of MDM2 and activates p53 in cancer cells that express the wild-type p53, leading to cell cycle arrest and growth inhibition. Crystal structures reveal that compound 19 induces MDM2 dimerization via the aliphatic linker. This unique dimerization-binding mode opens new prospects for the optimization of the p53-MDM2/MDMX inhibitors and conjugation with bioactive carriers.

-	~~Authors~~:	+	1,4,5-Trisubstituted Imidazole-Based p53-MDM2/MDMX Antagonists with Aliphatic Linkers for Conjugation with Biological Carriers.,Twarda-Clapa A, Krzanik S, Kubica K, Guzik K, Labuzek B, Neochoritis CG, Khoury K, Kowalska K, Czub M, Dubin G, Domling A, Skalniak L, Holak TA J Med Chem. 2017 May 16. doi: 10.1021/acs.jmedchem.7b00104. PMID:28482147<ref>PMID:28482147</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
		+	<div class="pdbe-citations 5j7g" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Dubin, G]]
		+	[[Category: Guzik, K]]
		+	[[Category: Holak, T A]]
		+	[[Category: Kubica, K]]
		+	[[Category: Twarda-Clapa, A]]
		+	[[Category: Cancer]]
		+	[[Category: Inhibitor]]
		+	[[Category: Ligase]]
		+	[[Category: Mdm2]]
		+	[[Category: Mdmx]]
		+	[[Category: P53]]
		+	[[Category: Protein-protein interaction]]

OCA at 07:52, 5 April 2017

OCA — Wed, 05 Apr 2017 07:52:31 GMT

←Older revision		Revision as of 07:52, 5 April 2017
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5j7g is ON HOLD until ~~Apr~~ 06 2018	+	The entry 5j7g is ON HOLD until Jul 06 2018

	Authors:		Authors:

OCA at 15:08, 15 May 2016

OCA — Sun, 15 May 2016 15:08:27 GMT

←Older revision		Revision as of 15:08, 15 May 2016
Line 3:		Line 3:
	The entry 5j7g is ON HOLD until Apr 06 2018		The entry 5j7g is ON HOLD until Apr 06 2018

-	Authors: ~~Twarda, A., Kubica, K., Guzik, K., Dubin, G., Holak, T.A.~~	+	Authors:

	Description:		Description:
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Holak, T.A]]
-	[[Category: Twarda, A]]
-	[[Category: Dubin, G]]
-	[[Category: Kubica, K]]
-	[[Category: Guzik, K]]

OCA: Protected "5j7g" [edit=sysop:move=sysop]

OCA — Wed, 11 May 2016 01:37:46 GMT

Protected "5j7g" [edit=sysop:move=sysop]

←Older revision

Revision as of 01:37, 11 May 2016

OCA: New page: '''Unreleased structure''' The entry 5j7g is ON HOLD until Apr 06 2018 Authors: Twarda, A., Kubica, K., Guzik, K., Dubin, G., Holak, T.A. Description: [[Category: Unreleased Structure...

OCA — Wed, 11 May 2016 01:37:44 GMT

New page: '''Unreleased structure''' The entry 5j7g is ON HOLD until Apr 06 2018 Authors: Twarda, A., Kubica, K., Guzik, K., Dubin, G., Holak, T.A. Description: [[Category: Unreleased Structure...

New page

'''Unreleased structure'''

The entry 5j7g is ON HOLD until Apr 06 2018

Authors: Twarda, A., Kubica, K., Guzik, K., Dubin, G., Holak, T.A.

Description:
[[Category: Unreleased Structures]]
[[Category: Holak, T.A]]
[[Category: Twarda, A]]
[[Category: Dubin, G]]
[[Category: Kubica, K]]
[[Category: Guzik, K]]