4umn - Revision history

OCA at 07:47, 7 February 2024

OCA — Wed, 07 Feb 2024 07:47:29 GMT

←Older revision		Revision as of 07:47, 7 February 2024
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	== Function ==		== Function ==
	[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>		[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;">
-	== Publication Abstract from PubMed ==
-	As key negative regulator of the p53 tumour suppressor, Mdm2 is an attractive therapeutic target. Small molecules such as Nutlin have been developed to antagonise Mdm2, resulting in p53-dependent death of tumour cells. We have recently described a mutation in Mdm2 (M62A), which precludes binding of Nutlin, but not p53. This Nutlin-resistant variant is not, however, refractory to binding and inhibition by stapled peptide antagonists targeting the same region of Mdm2. A detailed understanding of how stapled peptides are recalcitrant to Mdm2 mutations conferring Nutlin-resistance will aid in the further development of potent Mdm2 antagonists. Here, we report the 2.00 A crystal structure of a stapled peptide antagonist bound to Nutlin resistant Mdm2. The stapled peptide relies on an extended network of interactions along the hydrophobic binding cleft of Mdm2 for high affinity binding. Additionally, as seen in other stapled peptide structures, the hydrocarbon staple itself contributes to binding through favourable interactions with Mdm2. The structure highlights the intrinsic plasticity present in both Mdm2 and the hydrocarbon staple moiety, and can be used to guide future iterations of both small molecules and stapled peptides for improved antagonists of Mdm2.
-
-	Structure of a stapled Peptide antagonist bound to nutlin-resistant mdm2.,Chee SM, Wongsantichon J, Soo Tng Q, Robinson R, Joseph TL, Verma C, Lane DP, Brown CJ, Ghadessy FJ PLoS One. 2014 Aug 12;9(8):e104914. doi: 10.1371/journal.pone.0104914., eCollection 2014. PMID:25115702<ref>PMID:25115702</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 4umn" style="background-color:#fffaf0;"></div>

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

OCA at 09:23, 15 November 2023

OCA — Wed, 15 Nov 2023 09:23:05 GMT

←Older revision		Revision as of 09:23, 15 November 2023
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	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4umn]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UMN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4UMN FirstGlance]. <br>		<table><tr><td colspan='2'>[[4umn]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UMN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4UMN FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0EH:(2R)-2-AMINO-2-METHYLNONANOIC+ACID'>0EH</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=MK8:2-METHYL-L-NORLEUCINE'>MK8</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</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]] 1.99Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0EH:(2R)-2-AMINO-2-METHYLNONANOIC+ACID'>0EH</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=MK8:2-METHYL-L-NORLEUCINE'>MK8</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</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=4umn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4umn OCA], [https://pdbe.org/4umn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4umn RCSB], [https://www.ebi.ac.uk/pdbsum/4umn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4umn 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=4umn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4umn OCA], [https://pdbe.org/4umn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4umn RCSB], [https://www.ebi.ac.uk/pdbsum/4umn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4umn ProSAT]</span></td></tr>
	</table>		</table>

OCA at 09:56, 15 March 2023

OCA — Wed, 15 Mar 2023 09:56:15 GMT

←Older revision		Revision as of 09:56, 15 March 2023
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	<StructureSection load='4umn' size='340' side='right'caption='[[4umn]], [[Resolution\|resolution]] 1.99Å' scene=''>		<StructureSection load='4umn' size='340' side='right'caption='[[4umn]], [[Resolution\|resolution]] 1.99Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4umn]] 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=4UMN OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4UMN FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4umn]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UMN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4UMN FirstGlance]. <br>
-	</td></tr><tr id='~~NonStdRes~~'><td class="sblockLbl"><b>[[~~Non-Standard_Residue~~\|~~NonStd Res~~:]]</b></td><td class="sblockDat"><scene name='pdbligand=0EH:(2R)-2-AMINO-2-METHYLNONANOIC+ACID'>0EH</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=MK8:2-METHYL-L-NORLEUCINE'>MK8</scene>, <scene name='pdbligand=~~NME~~:~~METHYLAMINE~~'>~~NME~~</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0EH:(2R)-2-AMINO-2-METHYLNONANOIC+ACID'>0EH</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=MK8:2-METHYL-L-NORLEUCINE'>MK8</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</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=4umn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4umn OCA], [~~http~~://pdbe.org/4umn PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4umn RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4umn PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4umn 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=4umn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4umn OCA], [https://pdbe.org/4umn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4umn RCSB], [https://www.ebi.ac.uk/pdbsum/4umn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4umn 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 22:		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: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Brown~~, C J~~]]	+	[[Category: Synthetic construct]]
-	[[Category: Chee, S]]	+	[[Category: Brown CJ]]
-	[[Category: Ghadessy~~, F J~~]]	+	[[Category: Chee S]]
-	[[Category: Lane~~, D P~~]]	+	[[Category: Ghadessy FJ]]
-	[[Category: Quah, S]]	+	[[Category: Lane DP]]
-	[[Category: Robinson~~, R C~~]]	+	[[Category: Quah S]]
-	[[Category: Verma, C]]	+	[[Category: Robinson RC]]
-	[[Category: Wongsantichon, J]]	+	[[Category: Verma C]]
-	~~[[Category: Cell cycle~~]]	+	[[Category: Wongsantichon J]]

OCA at 06:18, 16 October 2019

OCA — Wed, 16 Oct 2019 06:18:01 GMT

←Older revision		Revision as of 06:18, 16 October 2019
Line 3:		Line 3:
	<StructureSection load='4umn' size='340' side='right'caption='[[4umn]], [[Resolution\|resolution]] 1.99Å' scene=''>		<StructureSection load='4umn' size='340' side='right'caption='[[4umn]], [[Resolution\|resolution]] 1.99Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4umn]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UMN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4UMN FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4umn]] 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=4UMN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4UMN FirstGlance]. <br>
	</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=0EH:(2R)-2-AMINO-2-METHYLNONANOIC+ACID'>0EH</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=MK8:2-METHYL-L-NORLEUCINE'>MK8</scene>, <scene name='pdbligand=NME:METHYLAMINE'>NME</scene></td></tr>		</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=0EH:(2R)-2-AMINO-2-METHYLNONANOIC+ACID'>0EH</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=MK8:2-METHYL-L-NORLEUCINE'>MK8</scene>, <scene name='pdbligand=NME:METHYLAMINE'>NME</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=4umn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4umn OCA], [http://pdbe.org/4umn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4umn RCSB], [http://www.ebi.ac.uk/pdbsum/4umn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4umn 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=4umn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4umn OCA], [http://pdbe.org/4umn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4umn RCSB], [http://www.ebi.ac.uk/pdbsum/4umn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4umn ProSAT]</span></td></tr>
Line 27:		Line 27:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Brown, C J]]		[[Category: Brown, C J]]

OCA at 07:18, 10 July 2019

OCA — Wed, 10 Jul 2019 07:18:28 GMT

←Older revision		Revision as of 07:18, 10 July 2019
Line 1:		Line 1:

	==Structure of a stapled peptide antagonist bound to Nutlin-resistant Mdm2.==		==Structure of a stapled peptide antagonist bound to Nutlin-resistant Mdm2.==
-	<StructureSection load='4umn' size='340' side='right' caption='[[4umn]], [[Resolution\|resolution]] 1.99Å' scene=''>	+	<StructureSection load='4umn' size='340' side='right'caption='[[4umn]], [[Resolution\|resolution]] 1.99Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4umn]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UMN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4UMN FirstGlance]. <br>		<table><tr><td colspan='2'>[[4umn]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UMN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4UMN FirstGlance]. <br>
Line 27:		Line 27:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Large Structures]]
	[[Category: Brown, C J]]		[[Category: Brown, C J]]
	[[Category: Chee, S]]		[[Category: Chee, S]]

OCA at 21:10, 11 August 2016

OCA — Thu, 11 Aug 2016 21:10:40 GMT

←Older revision		Revision as of 21:10, 11 August 2016
Line 1:		Line 1:
		+
	==Structure of a stapled peptide antagonist bound to Nutlin-resistant Mdm2.==		==Structure of a stapled peptide antagonist bound to Nutlin-resistant Mdm2.==
	<StructureSection load='4umn' size='340' side='right' caption='[[4umn]], [[Resolution\|resolution]] 1.99Å' scene=''>		<StructureSection load='4umn' size='340' side='right' caption='[[4umn]], [[Resolution\|resolution]] 1.99Å' scene=''>
Line 4:		Line 5:
	<table><tr><td colspan='2'>[[4umn]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UMN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4UMN FirstGlance]. <br>		<table><tr><td colspan='2'>[[4umn]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UMN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4UMN FirstGlance]. <br>
	</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=0EH:(2R)-2-AMINO-2-METHYLNONANOIC+ACID'>0EH</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=MK8:2-METHYL-L-NORLEUCINE'>MK8</scene>, <scene name='pdbligand=NME:METHYLAMINE'>NME</scene></td></tr>		</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=0EH:(2R)-2-AMINO-2-METHYLNONANOIC+ACID'>0EH</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=MK8:2-METHYL-L-NORLEUCINE'>MK8</scene>, <scene name='pdbligand=NME:METHYLAMINE'>NME</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=4umn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4umn OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4umn RCSB], [http://www.ebi.ac.uk/pdbsum/4umn 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=4umn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4umn OCA], [http://pdbe.org/4umn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4umn RCSB], [http://www.ebi.ac.uk/pdbsum/4umn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4umn ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 18:		Line 19:
	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 4umn" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[MDM2\|MDM2]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 14:49, 5 January 2015

OCA — Mon, 05 Jan 2015 14:49:14 GMT

←Older revision		Revision as of 14:49, 5 January 2015
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4umn]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UMN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4UMN FirstGlance]. <br>		<table><tr><td colspan='2'>[[4umn]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UMN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4UMN FirstGlance]. <br>
-	</td></tr><tr><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=0EH:(2R)-2-AMINO-2-METHYLNONANOIC+ACID'>0EH</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=MK8:2-METHYL-L-NORLEUCINE'>MK8</scene>, <scene name='pdbligand=NME:METHYLAMINE'>NME</scene></td></tr>	+	</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=0EH:(2R)-2-AMINO-2-METHYLNONANOIC+ACID'>0EH</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=MK8:2-METHYL-L-NORLEUCINE'>MK8</scene>, <scene name='pdbligand=NME:METHYLAMINE'>NME</scene></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=4umn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4umn OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4umn RCSB], [http://www.ebi.ac.uk/pdbsum/4umn 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=4umn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4umn OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4umn RCSB], [http://www.ebi.ac.uk/pdbsum/4umn 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 22:		Line 22:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: Brown, C J.]]	+	[[Category: Brown, C J]]
-	[[Category: Chee, S.]]	+	[[Category: Chee, S]]
-	[[Category: Ghadessy, F J.]]	+	[[Category: Ghadessy, F J]]
-	[[Category: Lane, D P.]]	+	[[Category: Lane, D P]]
-	[[Category: Quah, S.]]	+	[[Category: Quah, S]]
-	[[Category: Robinson, R C.]]	+	[[Category: Robinson, R C]]
-	[[Category: Verma, C.]]	+	[[Category: Verma, C]]
-	[[Category: Wongsantichon, J.]]	+	[[Category: Wongsantichon, J]]
	[[Category: Cell cycle]]		[[Category: Cell cycle]]

OCA at 05:55, 27 August 2014

OCA — Wed, 27 Aug 2014 05:55:42 GMT

←Older revision		Revision as of 05:55, 27 August 2014
Line 10:		Line 10:
	== 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 ==
		+	As key negative regulator of the p53 tumour suppressor, Mdm2 is an attractive therapeutic target. Small molecules such as Nutlin have been developed to antagonise Mdm2, resulting in p53-dependent death of tumour cells. We have recently described a mutation in Mdm2 (M62A), which precludes binding of Nutlin, but not p53. This Nutlin-resistant variant is not, however, refractory to binding and inhibition by stapled peptide antagonists targeting the same region of Mdm2. A detailed understanding of how stapled peptides are recalcitrant to Mdm2 mutations conferring Nutlin-resistance will aid in the further development of potent Mdm2 antagonists. Here, we report the 2.00 A crystal structure of a stapled peptide antagonist bound to Nutlin resistant Mdm2. The stapled peptide relies on an extended network of interactions along the hydrophobic binding cleft of Mdm2 for high affinity binding. Additionally, as seen in other stapled peptide structures, the hydrocarbon staple itself contributes to binding through favourable interactions with Mdm2. The structure highlights the intrinsic plasticity present in both Mdm2 and the hydrocarbon staple moiety, and can be used to guide future iterations of both small molecules and stapled peptides for improved antagonists of Mdm2.
		+
		+	Structure of a stapled Peptide antagonist bound to nutlin-resistant mdm2.,Chee SM, Wongsantichon J, Soo Tng Q, Robinson R, Joseph TL, Verma C, Lane DP, Brown CJ, Ghadessy FJ PLoS One. 2014 Aug 12;9(8):e104914. doi: 10.1371/journal.pone.0104914., eCollection 2014. PMID:25115702<ref>PMID:25115702</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
	== References ==		== References ==
	<references/>		<references/>

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

OCA — Wed, 28 May 2014 10:12:54 GMT

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

←Older revision

Revision as of 10:12, 28 May 2014

OCA: New page: ==Structure of a stapled peptide antagonist bound to Nutlin-resistant Mdm2.== == Structural highlights ==
<table><tr><td colspan='2'>[[4umn]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UMN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4UMN FirstGlance]. <br>
</td></tr><tr><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=0EH:(2R)-2-AMINO-2-METHYLNONANOIC+ACID'>0EH</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=MK8:2-METHYL-L-NORLEUCINE'>MK8</scene>, <scene name='pdbligand=NME:METHYLAMINE'>NME</scene></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=4umn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4umn OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4umn RCSB], [http://www.ebi.ac.uk/pdbsum/4umn 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.
== 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>
== References ==
<references/>
TOC
</StructureSection>
[[Category: Brown, C J.]]
[[Category: Chee, S.]]
[[Category: Ghadessy, F J.]]
[[Category: Lane, D P.]]
[[Category: Quah, S.]]
[[Category: Robinson, R C.]]
[[Category: Verma, C.]]
[[Category: Wongsantichon, J.]]
[[Category: Cell cycle]]