5law - Revision history

OCA at 16:13, 4 October 2023

OCA — Wed, 04 Oct 2023 16:13:33 GMT

←Older revision		Revision as of 16:13, 4 October 2023
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	<StructureSection load='5law' size='340' side='right'caption='[[5law]], [[Resolution\|resolution]] 1.64Å' scene=''>		<StructureSection load='5law' size='340' side='right'caption='[[5law]], [[Resolution\|resolution]] 1.64Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5law]] is a 1 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=5LAW OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5LAW FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5law]] 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=5LAW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5LAW FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6SJ:2-[(3~{S},3~{A}~{S},6~{S},6~{A}~{S})-6-CHLORANYL-6-(3-CHLOROPHENYL)-4-(CYCLOPROPYLMETHYL)-2-OXIDANYLIDENE-SPIRO[1~{H}-INDOLE-3,5-3,3~{A},6,6~{A}-TETRAHYDRO-2~{H}-PYRROLO[3,2-B]PYRROLE]-1-YL]ETHANOIC+ACID'>6SJ</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]] 1.64Å</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=5law FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5law OCA], [~~http~~://pdbe.org/5law PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5law RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5law PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5law ProSAT]</span></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6SJ:2-[(3~{S},3~{A}~{S},6~{S},6~{A}~{S})-6-CHLORANYL-6-(3-CHLOROPHENYL)-4-(CYCLOPROPYLMETHYL)-2-OXIDANYLIDENE-SPIRO[1~{H}-INDOLE-3,5-3,3~{A},6,6~{A}-TETRAHYDRO-2~{H}-PYRROLO[3,2-B]PYRROLE]-1-YL]ETHANOIC+ACID'>6SJ</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=5law FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5law OCA], [https://pdbe.org/5law PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5law RCSB], [https://www.ebi.ac.uk/pdbsum/5law PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5law 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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	==See Also==		==See Also==
-	*[[MDM2\|MDM2]]	+	*[[MDM2 3D structures\|MDM2 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
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	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Gollner, A]]	+	[[Category: Gollner A]]
-	[[Category: Kessler, D]]	+	[[Category: Kessler D]]
-	~~[[Category: Bi]]~~	+
-	~~[[Category: Hdm2]]~~	+
-	~~[[Category: Ligase]]~~	+
-	~~[[Category: Mdm2]]~~	+
-	~~[[Category: Ppi]]~~	+
-	~~[[Category: Vienna~~]]	+

OCA at 06:01, 12 June 2019

OCA — Wed, 12 Jun 2019 06:01:02 GMT

←Older revision		Revision as of 06:01, 12 June 2019
Line 1:		Line 1:

	==Novel Spiro[3H-indole-3,2 -pyrrolidin]-2(1H)-one Inhibitors of the MDM2-p53 Interaction: HDM2 (MDM2) IN COMPLEX WITH COMPOUND 14==		==Novel Spiro[3H-indole-3,2 -pyrrolidin]-2(1H)-one Inhibitors of the MDM2-p53 Interaction: HDM2 (MDM2) IN COMPLEX WITH COMPOUND 14==
-	<StructureSection load='5law' size='340' side='right' caption='[[5law]], [[Resolution\|resolution]] 1.64Å' scene=''>	+	<StructureSection load='5law' size='340' side='right'caption='[[5law]], [[Resolution\|resolution]] 1.64Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[5law]] is a 1 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=5LAW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LAW FirstGlance]. <br>		<table><tr><td colspan='2'>[[5law]] is a 1 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=5LAW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LAW FirstGlance]. <br>
Line 20:		Line 20:
	</div>		</div>
	<div class="pdbe-citations 5law" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5law" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[MDM2\|MDM2]]
	== References ==		== References ==
	<references/>		<references/>
Line 25:		Line 28:
	</StructureSection>		</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
-	[[Category: ~~GOLLNER~~, A]]	+	[[Category: Large Structures]]
-	[[Category: ~~KESSLER~~, D]]	+	[[Category: Gollner, A]]
		+	[[Category: Kessler, D]]
	[[Category: Bi]]		[[Category: Bi]]
	[[Category: Hdm2]]		[[Category: Hdm2]]

OCA at 18:18, 2 November 2016

OCA — Wed, 02 Nov 2016 18:18:07 GMT

←Older revision		Revision as of 18:18, 2 November 2016
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5law is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Novel Spiro[3H-indole-3,2 -pyrrolidin]-2(1H)-one Inhibitors of the MDM2-p53 Interaction: HDM2 (MDM2) IN COMPLEX WITH COMPOUND 14==
		+	<StructureSection load='5law' size='340' side='right' caption='[[5law]], [[Resolution\|resolution]] 1.64Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5law]] is a 1 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=5LAW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LAW FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6SJ:2-[(3~{S},3~{A}~{S},6~{S},6~{A}~{S})-6-CHLORANYL-6-(3-CHLOROPHENYL)-4-(CYCLOPROPYLMETHYL)-2-OXIDANYLIDENE-SPIRO[1~{H}-INDOLE-3,5-3,3~{A},6,6~{A}-TETRAHYDRO-2~{H}-PYRROLO[3,2-B]PYRROLE]-1-YL]ETHANOIC+ACID'>6SJ</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5law FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5law OCA], [http://pdbe.org/5law PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5law RCSB], [http://www.ebi.ac.uk/pdbsum/5law PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5law ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/MDM2_HUMAN MDM2_HUMAN]] Note=Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding.
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/MDM2_HUMAN MDM2_HUMAN]] E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as an ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and promotes it to proteasomal degradation.<ref>PMID:12821780</ref> <ref>PMID:15053880</ref> <ref>PMID:15195100</ref> <ref>PMID:16337594</ref> <ref>PMID:15632057</ref> <ref>PMID:17290220</ref> <ref>PMID:19098711</ref> <ref>PMID:19219073</ref> <ref>PMID:19965871</ref> <ref>PMID:20858735</ref> <ref>PMID:20173098</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Scaffold modification based on Wang s pioneering MDM2-p53 inhibitors led to novel, chemically stable spiro-oxindole compounds bearing a spiro[3H-indole-3,2 -pyrrolidin]-2(1H)-one scaffold that are not prone to epimerization as observed for the initial spiro[3H-indole-3,3 -pyrrolidin]-2(1H)-one scaffold. Further structure based optimization inspired by natural product architectures led to a complex fused ring system ideally suited to bind to the MDM2 protein and to interrupt its protein-protein interaction (PPI) with TP53. The compounds are highly selective and show in vivo efficacy in a SJSA-1 xenograft model even when given as a single dose as demonstrated for 4-[(3S,3'S,3'aS,5'R,6'aS)-6-chloro-3'-(3-chloro-2-fluorophenyl)-1'-(cyclopropylme thyl)-2-oxo-1,2,3',3'a,4',5',6',6'a-octahydro-1'H-spiro[indole-3,2'-pyrrolo[3,2-b ]pyrrole]-5'-yl]benzoic acid (BI-0252).

-	~~Authors: KESSLER~~, D., ~~GOLLNER~~, A.	+	Discovery of Novel Spiro[3H-indole-3,2 -pyrrolidin]-2(1H)-one Compounds as Chemically Stable, and Orally Active Inhibitors of the MDM2-p53 Interaction.,Gollner A, Rudolph D, Arnhof H, Bauer M, Blake SM, Boehmelt G, Cockcroft XL, Dahmann G, Ettmayer P, Gerstberger T, Karolyi-Oezguer J, Kessler D, Kofink C, Ramharter J, Rinnenthal J, Savchenko A, Schnitzer R, Weinstabl H, Weyer-Czernilofsky U, Wunberg T, McConnell DB J Med Chem. 2016 Oct 24. PMID:27775892<ref>PMID:27775892</ref>

-	~~Description: Discovery of New Natural-product-inspired Spiro-oxindole Compounds as Orally Active Inhibitors~~ of the ~~MDM2~~-~~p53 Interaction~~: ~~HDM2 (MDM2) IN COMPLEX WITH COMPOUND 14~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
-	[[Category: ~~Gollner~~, A]]	+	<div class="pdbe-citations 5law" style="background-color:#fffaf0;"></div>
-	[[Category: ~~Kessler~~, D]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: GOLLNER, A]]
		+	[[Category: KESSLER, D]]
		+	[[Category: Bi]]
		+	[[Category: Hdm2]]
		+	[[Category: Ligase]]
		+	[[Category: Mdm2]]
		+	[[Category: Ppi]]
		+	[[Category: Vienna]]

OCA at 00:54, 13 July 2016

OCA — Wed, 13 Jul 2016 00:54:04 GMT

←Older revision		Revision as of 00:54, 13 July 2016
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5law is ON HOLD	+	The entry 5law is ON HOLD until Paper Publication

	Authors: KESSLER, D., GOLLNER, A.		Authors: KESSLER, D., GOLLNER, A.

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

OCA — Thu, 23 Jun 2016 21:57:47 GMT

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

←Older revision

Revision as of 21:57, 23 June 2016

OCA: New page: '''Unreleased structure''' The entry 5law is ON HOLD Authors: KESSLER, D., GOLLNER, A. Description: Discovery of New Natural-product-inspired Spiro-oxindole Compounds as Orally Active ...

OCA — Thu, 23 Jun 2016 21:57:46 GMT

New page: '''Unreleased structure''' The entry 5law is ON HOLD Authors: KESSLER, D., GOLLNER, A. Description: Discovery of New Natural-product-inspired Spiro-oxindole Compounds as Orally Active ...

New page

'''Unreleased structure'''

The entry 5law is ON HOLD

Authors: KESSLER, D., GOLLNER, A.

Description: Discovery of New Natural-product-inspired Spiro-oxindole Compounds as Orally Active Inhibitors of the MDM2-p53 Interaction: HDM2 (MDM2) IN COMPLEX WITH COMPOUND 14
[[Category: Unreleased Structures]]
[[Category: Gollner, A]]
[[Category: Kessler, D]]