4ode - Revision history

OCA at 17:10, 20 September 2023

2023-09-20T17:10:38Z

← Older revision		Revision as of 17:10, 20 September 2023
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	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4ode]] 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=4ODE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ODE FirstGlance]. <br>		<table><tr><td colspan='2'>[[4ode]] 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=4ODE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ODE FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2U0:(2-{[(3R,5R,6S)-1-[(1S)-2-(TERT-BUTYLSULFONYL)-1-CYCLOPROPYLETHYL]-6-(4-CHLORO-3-FLUOROPHENYL)-5-(3-CHLOROPHENYL)-3-METHYL-2-OXOPIPERIDIN-3-YL]METHYL}-1,3-THIAZOL-5-YL)ACETIC+ACID'>2U0</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.8Å</td></tr>
			<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2U0:(2-{[(3R,5R,6S)-1-[(1S)-2-(TERT-BUTYLSULFONYL)-1-CYCLOPROPYLETHYL]-6-(4-CHLORO-3-FLUOROPHENYL)-5-(3-CHLOROPHENYL)-3-METHYL-2-OXOPIPERIDIN-3-YL]METHYL}-1,3-THIAZOL-5-YL)ACETIC+ACID'>2U0</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=4ode FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ode OCA], [https://pdbe.org/4ode PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ode RCSB], [https://www.ebi.ac.uk/pdbsum/4ode PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ode 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=4ode FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ode OCA], [https://pdbe.org/4ode PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ode RCSB], [https://www.ebi.ac.uk/pdbsum/4ode PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ode ProSAT]</span></td></tr>
	</table>		</table>

OCA at 07:18, 25 January 2023

2023-01-25T07:18:30Z

← Older revision		Revision as of 07:18, 25 January 2023
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	==Co-Crystal Structure of MDM2 with Inhibitor Compound 4==		==Co-Crystal Structure of MDM2 with Inhibitor Compound 4==
	<StructureSection load='4ode' size='340' side='right' caption='[[4ode]], [[Resolution\|resolution]] 1.80Å' scene=''>		<StructureSection load='4ode' size='340' side='right'caption='[[4ode]], [[Resolution\|resolution]] 1.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4ode]] 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=4ODE OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4ODE FirstGlance]. <br>		<table><tr><td colspan='2'>[[4ode]] 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=4ODE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ODE FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2U0:(2-{[(3R,5R,6S)-1-[(1S)-2-(TERT-BUTYLSULFONYL)-1-CYCLOPROPYLETHYL]-6-(4-CHLORO-3-FLUOROPHENYL)-5-(3-CHLOROPHENYL)-3-METHYL-2-OXOPIPERIDIN-3-YL]METHYL}-1,3-THIAZOL-5-YL)ACETIC+ACID'>2U0</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>~~</td></tr>~~		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2U0:(2-{[(3R,5R,6S)-1-[(1S)-2-(TERT-BUTYLSULFONYL)-1-CYCLOPROPYLETHYL]-6-(4-CHLORO-3-FLUOROPHENYL)-5-(3-CHLOROPHENYL)-3-METHYL-2-OXOPIPERIDIN-3-YL]METHYL}-1,3-THIAZOL-5-YL)ACETIC+ACID'>2U0</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">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'>[https://proteopedia.org/fgij/fg.htm?mol=4ode FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ode OCA], [https://pdbe.org/4ode PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ode RCSB], [https://www.ebi.ac.uk/pdbsum/4ode PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ode 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=4ode FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ode OCA], [~~http~~://pdbe.org/4ode PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4ode RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4ode PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4ode 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 ==
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	</div>		</div>
	<div class="pdbe-citations 4ode" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4ode" 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: ~~Huang, X~~]]		[[Category: Large Structures]]
	[[Category: ~~Long, A M~~]]		[[Category: Huang X]]
	[[Category: ~~Shaffer, P L~~]]		[[Category: Long AM]]
	[[Category: ~~Yakowec, P~~]]		[[Category: Shaffer PL]]
	[[Category: ~~Ligase-ligase inhibitor complex]]~~		[[Category: Yakowec P]]
	~~[[Category: P53]]~~
	~~[[Category: Protein-protein interaction~~]]

OCA at 08:24, 22 November 2017

2017-11-22T08:24:24Z

← Older revision		Revision as of 08:24, 22 November 2017
Line 21:		Line 21:
	</div>		</div>
	<div class="pdbe-citations 4ode" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4ode" style="background-color:#fffaf0;"></div>

	~~==See Also==~~
	*[[MDM2\|MDM2]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 16:24, 11 August 2016

2016-08-11T16:24:21Z

← Older revision		Revision as of 16:24, 11 August 2016
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	==Co-Crystal Structure of MDM2 with Inhibitor Compound 4==		==Co-Crystal Structure of MDM2 with Inhibitor Compound 4==
	<StructureSection load='4ode' size='340' side='right' caption='[[4ode]], [[Resolution\|resolution]] 1.80Å' scene=''>		<StructureSection load='4ode' size='340' side='right' caption='[[4ode]], [[Resolution\|resolution]] 1.80Å' scene=''>
Line 5:		Line 6:
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2U0:(2-{[(3R,5R,6S)-1-[(1S)-2-(TERT-BUTYLSULFONYL)-1-CYCLOPROPYLETHYL]-6-(4-CHLORO-3-FLUOROPHENYL)-5-(3-CHLOROPHENYL)-3-METHYL-2-OXOPIPERIDIN-3-YL]METHYL}-1,3-THIAZOL-5-YL)ACETIC+ACID'>2U0</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2U0:(2-{[(3R,5R,6S)-1-[(1S)-2-(TERT-BUTYLSULFONYL)-1-CYCLOPROPYLETHYL]-6-(4-CHLORO-3-FLUOROPHENYL)-5-(3-CHLOROPHENYL)-3-METHYL-2-OXOPIPERIDIN-3-YL]METHYL}-1,3-THIAZOL-5-YL)ACETIC+ACID'>2U0</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">MDM2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4ode FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ode OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ode RCSB], [http://www.ebi.ac.uk/pdbsum/4ode PDBsum]</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=4ode FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ode OCA], [http://pdbe.org/4ode PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ode RCSB], [http://www.ebi.ac.uk/pdbsum/4ode PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ode ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 19:		Line 20:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
			<div class="pdbe-citations 4ode" style="background-color:#fffaf0;"></div>

			==See Also==
			*[[MDM2\|MDM2]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 08:55, 5 January 2015

2015-01-05T08:55:02Z

← Older revision		Revision as of 08:55, 5 January 2015
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4ode]] 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=4ODE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ODE FirstGlance]. <br>		<table><tr><td colspan='2'>[[4ode]] 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=4ODE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ODE FirstGlance]. <br>
	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2U0:(2-{[(3R,5R,6S)-1-[(1S)-2-(TERT-BUTYLSULFONYL)-1-CYCLOPROPYLETHYL]-6-(4-CHLORO-3-FLUOROPHENYL)-5-(3-CHLOROPHENYL)-3-METHYL-2-OXOPIPERIDIN-3-YL]METHYL}-1,3-THIAZOL-5-YL)ACETIC+ACID'>2U0</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene><br>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2U0:(2-{[(3R,5R,6S)-1-[(1S)-2-(TERT-BUTYLSULFONYL)-1-CYCLOPROPYLETHYL]-6-(4-CHLORO-3-FLUOROPHENYL)-5-(3-CHLOROPHENYL)-3-METHYL-2-OXOPIPERIDIN-3-YL]METHYL}-1,3-THIAZOL-5-YL)ACETIC+ACID'>2U0</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
	<tr><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='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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ode FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ode OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ode RCSB], [http://www.ebi.ac.uk/pdbsum/4ode PDBsum]</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=4ode FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ode OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ode RCSB], [http://www.ebi.ac.uk/pdbsum/4ode PDBsum]</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.		[[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.
Line 24:		Line 24:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
	[[Category: Huang, X.]]		[[Category: Huang, X]]
	[[Category: Long, A M.]]		[[Category: Long, A M]]
	[[Category: Shaffer, P L.]]		[[Category: Shaffer, P L]]
	[[Category: Yakowec, P.]]		[[Category: Yakowec, P]]
	[[Category: Ligase-ligase inhibitor complex]]		[[Category: Ligase-ligase inhibitor complex]]
	[[Category: P53]]		[[Category: P53]]
	[[Category: Protein-protein interaction]]		[[Category: Protein-protein interaction]]

OCA at 05:27, 18 June 2014

2014-06-18T05:27:21Z

← Older revision		Revision as of 05:27, 18 June 2014
Line 1:		Line 1:
	~~{{STRUCTURE_4ode\| PDB=4ode \| SCENE= }}~~		==Co-Crystal Structure of MDM2 with Inhibitor Compound 4==
	===Co-Crystal Structure of MDM2 with Inhibitor Compound 4===		<StructureSection load='4ode' size='340' side='right' caption='[[4ode]], [[Resolution\|resolution]] 1.80Å' scene=''>
	{~~{ABSTRACT_PUBMED_24601644}~~}		== Structural highlights ==
			<table><tr><td colspan='2'>[[4ode]] 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=4ODE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ODE FirstGlance]. <br>
	==Disease==		</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2U0:(2-{[(3R,5R,6S)-1-[(1S)-2-(TERT-BUTYLSULFONYL)-1-CYCLOPROPYLETHYL]-6-(4-CHLORO-3-FLUOROPHENYL)-5-(3-CHLOROPHENYL)-3-METHYL-2-OXOPIPERIDIN-3-YL]METHYL}-1,3-THIAZOL-5-YL)ACETIC+ACID'>2U0</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene><br>
			<tr><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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ode FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ode OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ode RCSB], [http://www.ebi.ac.uk/pdbsum/4ode PDBsum]</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.		[[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 ==
	==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>		[[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 ==
			We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogues. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts toward the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.

	~~==About this Structure==~~		Novel Inhibitors of the MDM2-p53 Interaction Featuring Hydrogen Bond Acceptors as Carboxylic Acid Isosteres.,Gonzalez AZ, Li Z, Beck HP, Canon J, Chen A, Chow D, Duquette J, Eksterowicz J, Fox BM, Fu J, Huang X, Houze J, Jin L, Li Y, Ling Y, Lo MC, Long AM, McGee LR, McIntosh J, Oliner JD, Osgood T, Rew Y, Saiki AY, Shaffer P, Wortman S, Yakowec P, Yan X, Ye Q, Yu D, Zhao X, Zhou J, Olson SH, Sun D, Medina JC J Med Chem. 2014 Mar 27. PMID:24601644<ref>PMID:24601644</ref>
	~~[[4ode]] is a 1 chain structure~~. ~~Full crystallographic information is available from [http://oca~~.~~weizmann~~.~~ac.il~~/~~oca-bin/ocashort?id=4ODE OCA].~~

	==~~Reference~~==		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	~~<ref group="xtra">PMID:024601644</ref>~~<references ~~group="xtra"~~/><~~references~~/>		</div>
			== References ==
			<references/>
			__TOC__
			</StructureSection>
			[[Category: Human]]
	[[Category: Huang, X.]]		[[Category: Huang, X.]]
	[[Category: Long, A M.]]		[[Category: Long, A M.]]

OCA at 09:12, 2 April 2014

2014-04-02T09:12:41Z

← Older revision		Revision as of 09:12, 2 April 2014
Line 1:		Line 1:
	~~'''Unreleased structure'''~~		{{STRUCTURE_4ode\| PDB=4ode \| SCENE= }}
			===Co-Crystal Structure of MDM2 with Inhibitor Compound 4===
			{{ABSTRACT_PUBMED_24601644}}

	~~The entry 4ode is ON HOLD until Paper Publication~~		==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.

	~~Authors~~: ~~Shaffer~~, P.L.~~, Huang, X~~.~~, Yakowec, P~~.~~, Long, A~~.M.		==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>

	~~Description~~: Co-~~Crystal Structure of MDM2 with Inhibitor Compound 4~~		==About this Structure==
			[[4ode]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ODE OCA].

			==Reference==
			<ref group="xtra">PMID:024601644</ref><references group="xtra"/><references/>
			[[Category: Huang, X.]]
			[[Category: Long, A M.]]
			[[Category: Shaffer, P L.]]
			[[Category: Yakowec, P.]]
			[[Category: Ligase-ligase inhibitor complex]]
			[[Category: P53]]
			[[Category: Protein-protein interaction]]

OCA at 04:50, 13 February 2014

2014-02-13T04:50:23Z

← Older revision		Revision as of 04:50, 13 February 2014
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 4ode is ON HOLD		The entry 4ode is ON HOLD until Paper Publication

	Authors: Shaffer, P.L., Huang, X., Yakowec, P., Long, A.M.		Authors: Shaffer, P.L., Huang, X., Yakowec, P., Long, A.M.

	Description: Co-Crystal Structure of MDM2 with Inhibitor Compound 4		Description: Co-Crystal Structure of MDM2 with Inhibitor Compound 4

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

2014-01-22T06:47:19Z

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

← Older revision	Revision as of 06:47, 22 January 2014
(No difference)

OCA: New page: '''Unreleased structure''' The entry 4ode is ON HOLD Authors: Shaffer, P.L., Huang, X., Yakowec, P., Long, A.M. Description: Co-Crystal Structure of MDM2 with Inhibitor Compound 4

2014-01-22T06:47:19Z

New page: '''Unreleased structure''' The entry 4ode is ON HOLD Authors: Shaffer, P.L., Huang, X., Yakowec, P., Long, A.M. Description: Co-Crystal Structure of MDM2 with Inhibitor Compound 4

New page

'''Unreleased structure'''

The entry 4ode is ON HOLD

Authors: Shaffer, P.L., Huang, X., Yakowec, P., Long, A.M.

Description: Co-Crystal Structure of MDM2 with Inhibitor Compound 4