4jwr - Revision history

OCA at 15:50, 20 September 2023

OCA — Wed, 20 Sep 2023 15:50:08 GMT

←Older revision		Revision as of 15:50, 20 September 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4jwr]] is a 3 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=4JWR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JWR FirstGlance]. <br>		<table><tr><td colspan='2'>[[4jwr]] is a 3 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=4JWR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JWR FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1MY:{(2S,5R,6S)-6-(3-CHLOROPHENYL)-5-(4-CHLOROPHENYL)-4-[(2S)-1-HYDROXYBUTAN-2-YL]-3-OXOMORPHOLIN-2-YL}ACETIC+ACID'>1MY</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]] 2.35Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1MY:{(2S,5R,6S)-6-(3-CHLOROPHENYL)-5-(4-CHLOROPHENYL)-4-[(2S)-1-HYDROXYBUTAN-2-YL]-3-OXOMORPHOLIN-2-YL}ACETIC+ACID'>1MY</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=4jwr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jwr OCA], [https://pdbe.org/4jwr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jwr RCSB], [https://www.ebi.ac.uk/pdbsum/4jwr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jwr 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=4jwr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jwr OCA], [https://pdbe.org/4jwr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jwr RCSB], [https://www.ebi.ac.uk/pdbsum/4jwr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jwr ProSAT]</span></td></tr>
	</table>		</table>

OCA at 11:28, 30 November 2022

OCA — Wed, 30 Nov 2022 11:28:40 GMT

←Older revision		Revision as of 11:28, 30 November 2022
Line 1:		Line 1:

	==Co-crystal structure of MDM2 with inhibitor {(2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-[(2S)-1-hydroxybutan-2-yl]-3-oxomorpholin-2-yl}acetic acid==		==Co-crystal structure of MDM2 with inhibitor {(2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-[(2S)-1-hydroxybutan-2-yl]-3-oxomorpholin-2-yl}acetic acid==
-	<StructureSection load='4jwr' size='340' side='right' caption='[[4jwr]], [[Resolution\|resolution]] 2.35Å' scene=''>	+	<StructureSection load='4jwr' size='340' side='right'caption='[[4jwr]], [[Resolution\|resolution]] 2.35Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4jwr]] is a 3 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=4JWR OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4JWR FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4jwr]] is a 3 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=4JWR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JWR FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1MY:{(2S,5R,6S)-6-(3-CHLOROPHENYL)-5-(4-CHLOROPHENYL)-4-[(2S)-1-HYDROXYBUTAN-2-YL]-3-OXOMORPHOLIN-2-YL}ACETIC+ACID'>1MY</scene>~~</td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1MY:{(2S,5R,6S)-6-(3-CHLOROPHENYL)-5-(4-CHLOROPHENYL)-4-[(2S)-1-HYDROXYBUTAN-2-YL]-3-OXOMORPHOLIN-2-YL}ACETIC+ACID'>1MY</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4jv9\|4jv9]], [[4jv7\|4jv7]], [[4jve\|4jve]], [[4jvr\|4jvr]]</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=4jwr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jwr OCA], [https://pdbe.org/4jwr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jwr RCSB], [https://www.ebi.ac.uk/pdbsum/4jwr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jwr ProSAT]</span></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=4jwr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jwr OCA], [~~http~~://pdbe.org/4jwr PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4jwr RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4jwr PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4jwr 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 24:		Line 22:

	==See Also==		==See Also==
-	*[[MDM2\|MDM2]]	+	*[[MDM2 3D structures\|MDM2 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Shaffer, P L~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Ligase-ligase inhibitor complex]]~~	+	[[Category: Shaffer PL]]
-	~~[[Category: P53]]~~	+
-	~~[[Category: Protein-protein interaction~~]]	+

OCA at 17:40, 5 August 2016

OCA — Fri, 05 Aug 2016 17:40:14 GMT

←Older revision		Revision as of 17:40, 5 August 2016
Line 1:		Line 1:
		+
	==Co-crystal structure of MDM2 with inhibitor {(2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-[(2S)-1-hydroxybutan-2-yl]-3-oxomorpholin-2-yl}acetic acid==		==Co-crystal structure of MDM2 with inhibitor {(2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-[(2S)-1-hydroxybutan-2-yl]-3-oxomorpholin-2-yl}acetic acid==
	<StructureSection load='4jwr' size='340' side='right' caption='[[4jwr]], [[Resolution\|resolution]] 2.35Å' scene=''>		<StructureSection load='4jwr' size='340' side='right' caption='[[4jwr]], [[Resolution\|resolution]] 2.35Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4jwr]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JWR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JWR FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4jwr]] is a 3 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=4JWR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JWR FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1MY:{(2S,5R,6S)-6-(3-CHLOROPHENYL)-5-(4-CHLOROPHENYL)-4-[(2S)-1-HYDROXYBUTAN-2-YL]-3-OXOMORPHOLIN-2-YL}ACETIC+ACID'>1MY</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1MY:{(2S,5R,6S)-6-(3-CHLOROPHENYL)-5-(4-CHLOROPHENYL)-4-[(2S)-1-HYDROXYBUTAN-2-YL]-3-OXOMORPHOLIN-2-YL}ACETIC+ACID'>1MY</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4jv9\|4jv9]], [[4jv7\|4jv7]], [[4jve\|4jve]], [[4jvr\|4jvr]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4jv9\|4jv9]], [[4jv7\|4jv7]], [[4jve\|4jve]], [[4jvr\|4jvr]]</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 ~~Homo sapiens~~])</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=4jwr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jwr OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4jwr RCSB], [http://www.ebi.ac.uk/pdbsum/4jwr 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=4jwr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jwr OCA], [http://pdbe.org/4jwr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4jwr RCSB], [http://www.ebi.ac.uk/pdbsum/4jwr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4jwr ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 20:		Line 21:
	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 4jwr" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 27:		Line 29:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
	[[Category: Shaffer, P L]]		[[Category: Shaffer, P L]]
	[[Category: Ligase-ligase inhibitor complex]]		[[Category: Ligase-ligase inhibitor complex]]
	[[Category: P53]]		[[Category: P53]]
	[[Category: Protein-protein interaction]]		[[Category: Protein-protein interaction]]

OCA at 15:26, 21 December 2014

OCA — Sun, 21 Dec 2014 15:26:07 GMT

←Older revision		Revision as of 15:26, 21 December 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_4jwr\| PDB=4jwr \| SCENE= }}~~	+	==Co-crystal structure of MDM2 with inhibitor {(2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-[(2S)-1-hydroxybutan-2-yl]-3-oxomorpholin-2-yl}acetic acid==
-	===Co-crystal structure of MDM2 with inhibitor {(2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-[(2S)-1-hydroxybutan-2-yl]-3-oxomorpholin-2-yl}acetic acid===	+	<StructureSection load='4jwr' size='340' side='right' caption='[[4jwr]], [[Resolution\|resolution]] 2.35Å' scene=''>
-	{~~{ABSTRACT_PUBMED_23597064}~~}	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[4jwr]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JWR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JWR FirstGlance]. <br>
-	==Disease==	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1MY:{(2S,5R,6S)-6-(3-CHLOROPHENYL)-5-(4-CHLOROPHENYL)-4-[(2S)-1-HYDROXYBUTAN-2-YL]-3-OXOMORPHOLIN-2-YL}ACETIC+ACID'>1MY</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4jv9\|4jv9]], [[4jv7\|4jv7]], [[4jve\|4jve]], [[4jvr\|4jvr]]</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 Homo sapiens])</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=4jwr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jwr OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4jwr RCSB], [http://www.ebi.ac.uk/pdbsum/4jwr 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 ==
		+	[[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 ==
		+	Structural analysis of both the MDM2-p53 protein-protein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone 10, an MDM2 inhibitor with a biochemical IC50 of 1.0 muM. The co-crystal structure of 10 with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones 16 and 27 possessing distinct binding modes. Both analogs were potent MDM2 inhibitors in biochemical and cellular assays, and morpholinone 27 (IC50 = 0.10 muM) also displayed suitable PK profile for in vivo animal experiments. A pharmacodynamic (PD) experiment in mice implanted with human SJSA-1 tumors showed p21 induction (2-fold over vehicle) upon oral dosing of 27 at 300 mg/kg.

-	~~==Function==~~	+	Rational Design and Binding Mode Duality of MDM2-p53 Inhibitors.,Gonzalez-Lopez de Turiso F, Sun D, Rew Y, Bartberger MD, Beck HP, Canon J, Chen A, Chow D, Correll TL, Huang X, Julian LD, Kayser F, Lo MC, Long AM, McMinn D, Oliner JD, Osgood T, Powers JP, Saiki AY, Schneider S, Shaffer P, Xiao SH, Yakowec P, Yan X, Ye Q, Yu D, Zhao X, Zhou J, Medina JC, Olson SH J Med Chem. 2013 Apr 18. PMID:23597064<ref>PMID:23597064</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>	+

-	~~==About this Structure==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[4jwr]] is~~ a ~~3 chain structure with sequence from [http://en~~.~~wikipedia~~.~~org/wiki/Homo_sapiens Homo sapiens]~~. ~~Full crystallographic information is available from [http:~~/~~/oca.weizmann.ac.il/oca-bin/ocashort?id=4JWR OCA].~~	+	</div>

-	==~~Reference~~==	+	==See Also==
-	~~<ref group~~=~~"xtra">PMID:023597064</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	*[[MDM2\|MDM2]]
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
-	[[Category: Shaffer, P L.]]	+	[[Category: Shaffer, P L]]
	[[Category: Ligase-ligase inhibitor complex]]		[[Category: Ligase-ligase inhibitor complex]]
	[[Category: P53]]		[[Category: P53]]
	[[Category: Protein-protein interaction]]		[[Category: Protein-protein interaction]]

OCA at 18:24, 19 June 2013

OCA — Wed, 19 Jun 2013 18:24:33 GMT

←Older revision		Revision as of 18:24, 19 June 2013
Line 13:		Line 13:

	==Reference==		==Reference==
-	<references group="xtra"/><references/>	+	<ref group="xtra">PMID:023597064</ref><references group="xtra"/><references/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Shaffer, P L.]]		[[Category: Shaffer, P L.]]

OCA at 07:38, 2 May 2013

OCA — Thu, 02 May 2013 07:38:10 GMT

←Older revision		Revision as of 07:38, 2 May 2013
Line 1:		Line 1:
-	~~'''Unreleased~~ structure~~'''~~	+	{{STRUCTURE_4jwr\| PDB=4jwr \| SCENE= }}
		+	===Co-crystal structure of MDM2 with inhibitor {(2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-[(2S)-1-hydroxybutan-2-yl]-3-oxomorpholin-2-yl}acetic acid===
		+	{{ABSTRACT_PUBMED_23597064}}

-	~~The entry 4jwr 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.	+	==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~~:	+	==About this Structure==
		+	[[4jwr]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JWR OCA].
		+
		+	==Reference==
		+	<references group="xtra"/><references/>
		+	[[Category: Homo sapiens]]
		+	[[Category: Shaffer, P L.]]
		+	[[Category: Ligase-ligase inhibitor complex]]
		+	[[Category: P53]]
		+	[[Category: Protein-protein interaction]]

OCA at 20:01, 17 April 2013

OCA — Wed, 17 Apr 2013 20:01:47 GMT

←Older revision		Revision as of 20:01, 17 April 2013
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

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

	Authors: Shaffer, P.L.		Authors: Shaffer, P.L.

-	Description: ~~Co-crystal Structure of MDM2 with Compound 28~~	+	Description:

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

OCA — Thu, 04 Apr 2013 01:07:11 GMT

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

←Older revision

Revision as of 01:07, 4 April 2013

OCA: New page: '''Unreleased structure''' The entry 4jwr is ON HOLD Authors: Shaffer, P.L. Description: Co-crystal Structure of MDM2 with Compound 28

OCA — Thu, 04 Apr 2013 01:07:09 GMT

New page: '''Unreleased structure''' The entry 4jwr is ON HOLD Authors: Shaffer, P.L. Description: Co-crystal Structure of MDM2 with Compound 28

New page

'''Unreleased structure'''

The entry 4jwr is ON HOLD

Authors: Shaffer, P.L.

Description: Co-crystal Structure of MDM2 with Compound 28