OCA at 08:31, 21 April 2021

OCA — Wed, 21 Apr 2021 08:31:31 GMT

←Older revision		Revision as of 08:31, 21 April 2021
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	==Inhibitor of MDM2-p53 Interaction==		==Inhibitor of MDM2-p53 Interaction==
-	<StructureSection load='7bj6' size='340' side='right'caption='[[7bj6]]' scene=''>	+	<StructureSection load='7bj6' size='340' side='right'caption='[[7bj6]], [[Resolution\|resolution]] 1.59Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7BJ6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7BJ6 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7bj6]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7BJ6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7BJ6 FirstGlance]. <br>
-	</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=7bj6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bj6 OCA], [https://pdbe.org/7bj6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bj6 RCSB], [https://www.ebi.ac.uk/pdbsum/7bj6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bj6 ProSAT]</span></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TVK:(3~{R})-2-[(5-chloranylpyridin-2-yl)methyl]-3-(4-chlorophenyl)-4-fluoranyl-3-[[1-(hydroxymethyl)cyclopropyl]methoxy]-6-(2-oxidanylpropan-2-yl)isoindol-1-one'>TVK</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">MDM2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/RING-type_E3_ubiquitin_transferase RING-type E3 ubiquitin transferase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.2.27 2.3.2.27] </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=7bj6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bj6 OCA], [https://pdbe.org/7bj6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bj6 RCSB], [https://www.ebi.ac.uk/pdbsum/7bj6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bj6 ProSAT]</span></td></tr>
	</table>		</table>
		+	== Disease ==
		+	[[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 ==
		+	[[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 ==
		+	Inhibition of murine double minute 2 (MDM2)-p53 protein-protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, quantum mechanics ligand-based design, and metabolite identification all contributed toward the discovery of potent in vitro and in vivo inhibitors of the MDM2-p53 interaction with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.
		+
		+	Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein-Protein Interaction.,Chessari G, Hardcastle IR, Ahn JS, Anil B, Anscombe E, Bawn RH, Bevan LD, Blackburn TJ, Buck I, Cano C, Carbain B, Castro J, Cons B, Cully SJ, Endicott JA, Fazal L, Golding BT, Griffin RJ, Haggerty K, Harnor SJ, Hearn K, Hobson S, Holvey RS, Howard S, Jennings CE, Johnson CN, Lunec J, Miller DC, Newell DR, Noble MEM, Reeks J, Revill CH, Riedinger C, St Denis JD, Tamanini E, Thomas H, Thompson NT, Vinkovic M, Wedge SR, Williams PA, Wilsher NE, Zhang B, Zhao Y J Med Chem. 2021 Mar 24. doi: 10.1021/acs.jmedchem.0c02188. PMID:33761253<ref>PMID:33761253</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7bj6" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Williams PA]]	+	[[Category: RING-type E3 ubiquitin transferase]]
		+	[[Category: Williams, P A]]
		+	[[Category: Apoptosis]]
		+	[[Category: Cell cycle]]
		+	[[Category: Ligase]]
		+	[[Category: Protein binding]]

OCA at 06:48, 7 April 2021

OCA — Wed, 07 Apr 2021 06:48:53 GMT

←Older revision		Revision as of 06:48, 7 April 2021
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-	'''Unreleased structure'''

-	~~The entry~~ 7bj6 ~~is ON HOLD until Paper Publication~~	+	==Inhibitor of MDM2-p53 Interaction==
-		+	<StructureSection load='7bj6' size='340' side='right'caption='[[7bj6]]' scene=''>
-	~~Authors~~: ~~Williams, P~~.A.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7BJ6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7BJ6 FirstGlance]. <br>
-	~~Description~~: ~~Inhibitor of MDM2~~-~~p53 Interaction~~	+	</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=7bj6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bj6 OCA], [https://pdbe.org/7bj6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bj6 RCSB], [https://www.ebi.ac.uk/pdbsum/7bj6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bj6 ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: Williams~~, P.A~~]]	+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Williams PA]]

OCA at 13:08, 3 March 2021

OCA — Wed, 03 Mar 2021 13:08:08 GMT

←Older revision		Revision as of 13:08, 3 March 2021
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7bj6 is ON HOLD	+	The entry 7bj6 is ON HOLD until Paper Publication

	Authors: Williams, P.A.		Authors: Williams, P.A.

OCA: Protected "7bj6" [edit=sysop:move=sysop]

OCA — Wed, 20 Jan 2021 06:43:28 GMT

Protected "7bj6" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:43, 20 January 2021

OCA: New page: '''Unreleased structure''' The entry 7bj6 is ON HOLD Authors: Williams, P.A. Description: Inhibitor of MDM2-p53 Interaction Category: Unreleased Structures [[Category: Williams, P....

OCA — Wed, 20 Jan 2021 06:43:27 GMT

New page: '''Unreleased structure''' The entry 7bj6 is ON HOLD Authors: Williams, P.A. Description: Inhibitor of MDM2-p53 Interaction Category: Unreleased Structures [[Category: Williams, P....

New page

'''Unreleased structure'''

The entry 7bj6 is ON HOLD

Authors: Williams, P.A.

Description: Inhibitor of MDM2-p53 Interaction
[[Category: Unreleased Structures]]
[[Category: Williams, P.A]]

7bj6 - Revision history

OCA at 08:31, 21 April 2021

OCA at 06:48, 7 April 2021

OCA at 13:08, 3 March 2021

OCA: Protected "7bj6" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 7bj6 is ON HOLD Authors: Williams, P.A. Description: Inhibitor of MDM2-p53 Interaction Category: Unreleased Structures [[Category: Williams, P....