2n14 - Revision history

OCA at 07:03, 1 May 2024

OCA — Wed, 01 May 2024 07:03:23 GMT

←Older revision		Revision as of 07:03, 1 May 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[2n14]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N14 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2N14 FirstGlance]. <br>		<table><tr><td colspan='2'>[[2n14]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N14 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2N14 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=49H:4-({(4S,5R)-4-(3-CHLOROPHENYL)-5-(4-CHLOROPHENYL)-2-[4-METHOXY-2-(PROPAN-2-YLOXY)PHENYL]-4,5-DIHYDRO-1H-IMIDAZOL-1-YL}CARBONYL)PIPERAZIN-2-ONE'>49H</scene></td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=49H:4-({(4S,5R)-4-(3-CHLOROPHENYL)-5-(4-CHLOROPHENYL)-2-[4-METHOXY-2-(PROPAN-2-YLOXY)PHENYL]-4,5-DIHYDRO-1H-IMIDAZOL-1-YL}CARBONYL)PIPERAZIN-2-ONE'>49H</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=2n14 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n14 OCA], [https://pdbe.org/2n14 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2n14 RCSB], [https://www.ebi.ac.uk/pdbsum/2n14 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2n14 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=2n14 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n14 OCA], [https://pdbe.org/2n14 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2n14 RCSB], [https://www.ebi.ac.uk/pdbsum/2n14 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2n14 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/MDM4_HUMAN MDM4_HUMAN] Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions.<ref>PMID:16163388</ref> <ref>PMID:16511572</ref>		[https://www.uniprot.org/uniprot/MDM4_HUMAN MDM4_HUMAN] Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions.<ref>PMID:16163388</ref> <ref>PMID:16511572</ref>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	While the gene for p53 is mutated in many human cancers causing loss of function, many others maintain a wild-type gene but exhibit reduced p53 tumor suppressor activity through overexpression of the negative regulators, Mdm2 and/or MdmX. For the latter mechanism of loss of function, the activity of endogenous p53 can be restored through inhibition of Mdm2 or MdmX with small molecules. We previously reported a series of compounds based upon the Nutlin-3 chemical scaffold that bind to both MdmX and Mdm2 [Vara, B. A. et al. (2014) Organocatalytic, diastereo- and enantioselective synthesis of nonsymmetric cis-stilbene diamines: A platform for the preparation of single-enantiomer cis-imidazolines for protein-protein inhibition. J. Org. Chem. 79, 6913-6938]. Here we present the first solution structures based on data from NMR spectroscopy for MdmX in complex with four of these compounds and compare them with the MdmX:p53 complex. A p53-derived peptide binds with high affinity (Kd value of 150nM) and causes the formation of an extensive network of hydrogen bonds within MdmX; this constitutes the induction of order within MdmX through ligand binding. In contrast, the compounds bind more weakly (Kd values from 600nM to 12muM) and induce an incomplete hydrogen bond network within MdmX. Despite relatively weak binding, the four compounds activated p53 and induced p21(Cip1) expression in retinoblastoma cell lines that overexpress MdmX, suggesting that they specifically target MdmX and/or Mdm2. Our results document structure-activity relationships for lead-like small molecules targeting MdmX and suggest a strategy for their further optimization in the future by using NMR spectroscopy to monitor small-molecule-induced protein order as manifested through hydrogen bond formation.
-
-	Monitoring Ligand-Induced Protein Ordering in Drug Discovery.,Grace CR, Ban D, Min J, Mayasundari A, Min L, Finch KE, Griffiths L, Bharatham N, Bashford D, Kiplin Guy R, Dyer MA, Kriwacki RW J Mol Biol. 2016 Mar 27;428(6):1290-303. doi: 10.1016/j.jmb.2016.01.016. Epub, 2016 Jan 23. PMID:26812210<ref>PMID:26812210</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 2n14" style="background-color:#fffaf0;"></div>

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

OCA at 08:13, 8 March 2023

OCA — Wed, 08 Mar 2023 08:13:26 GMT

←Older revision		Revision as of 08:13, 8 March 2023
Line 1:		Line 1:

	==Mdmx-295==		==Mdmx-295==
-	<StructureSection load='2n14' size='340' side='right'caption='[[2n14~~]], [[NMR_Ensembles_of_Models \| 20 NMR models~~]]' scene=''>	+	<StructureSection load='2n14' size='340' side='right'caption='[[2n14]]' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[2n14]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Human Human~~]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N14 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2N14 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[2n14]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N14 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2N14 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=49H:4-({(4S,5R)-4-(3-CHLOROPHENYL)-5-(4-CHLOROPHENYL)-2-[4-METHOXY-2-(PROPAN-2-YLOXY)PHENYL]-4,5-DIHYDRO-1H-IMIDAZOL-1-YL}CARBONYL)PIPERAZIN-2-ONE'>49H</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=49H:4-({(4S,5R)-4-(3-CHLOROPHENYL)-5-(4-CHLOROPHENYL)-2-[4-METHOXY-2-(PROPAN-2-YLOXY)PHENYL]-4,5-DIHYDRO-1H-IMIDAZOL-1-YL}CARBONYL)PIPERAZIN-2-ONE'>49H</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2n0u\|2n0u]], [[2n0w\|2n0w]], [[2n06\|2n06]]</div></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">MDM4, MDMX ([https://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=2n14 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n14 OCA], [https://pdbe.org/2n14 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2n14 RCSB], [https://www.ebi.ac.uk/pdbsum/2n14 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2n14 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=2n14 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n14 OCA], [https://pdbe.org/2n14 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2n14 RCSB], [https://www.ebi.ac.uk/pdbsum/2n14 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2n14 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/MDM4_HUMAN MDM4_HUMAN]] Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions.<ref>PMID:16163388</ref> <ref>PMID:16511572</ref>	+	[https://www.uniprot.org/uniprot/MDM4_HUMAN MDM4_HUMAN] Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions.<ref>PMID:16163388</ref> <ref>PMID:16511572</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 27:		Line 25:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Grace~~, C R~~]]	+	[[Category: Grace CR]]
-	[[Category: Kriwacki~~, R W]]~~	+	[[Category: Kriwacki RW]]
-	~~[[Category: Mdmx]]~~	+
-	~~[[Category: Signaling protein~~]]	+

OCA at 15:25, 2 June 2021

OCA — Wed, 02 Jun 2021 15:25:00 GMT

←Older revision		Revision as of 15:25, 2 June 2021
Line 1:		Line 1:

	==Mdmx-295==		==Mdmx-295==
-	<StructureSection load='2n14' size='340' side='right' caption='[[2n14]], [[NMR_Ensembles_of_Models \| 20 NMR models]]' scene=''>	+	<StructureSection load='2n14' size='340' side='right'caption='[[2n14]], [[NMR_Ensembles_of_Models \| 20 NMR models]]' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[2n14]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N14 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=2N14 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[2n14]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N14 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2N14 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=49H:4-({(4S,5R)-4-(3-CHLOROPHENYL)-5-(4-CHLOROPHENYL)-2-[4-METHOXY-2-(PROPAN-2-YLOXY)PHENYL]-4,5-DIHYDRO-1H-IMIDAZOL-1-YL}CARBONYL)PIPERAZIN-2-ONE'>49H</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=49H:4-({(4S,5R)-4-(3-CHLOROPHENYL)-5-(4-CHLOROPHENYL)-2-[4-METHOXY-2-(PROPAN-2-YLOXY)PHENYL]-4,5-DIHYDRO-1H-IMIDAZOL-1-YL}CARBONYL)PIPERAZIN-2-ONE'>49H</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2n0u\|2n0u]], [[2n0w\|2n0w]], [[2n06\|2n06]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2n0u\|2n0u]], [[2n0w\|2n0w]], [[2n06\|2n06]]</div></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">MDM4, MDMX ([~~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">MDM4, MDMX ([https://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=2n14 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n14 OCA], [~~http~~://pdbe.org/2n14 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=2n14 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/2n14 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=2n14 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=2n14 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n14 OCA], [https://pdbe.org/2n14 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2n14 RCSB], [https://www.ebi.ac.uk/pdbsum/2n14 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2n14 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/MDM4_HUMAN MDM4_HUMAN]] Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions.<ref>PMID:16163388</ref> <ref>PMID:16511572</ref>	+	[[https://www.uniprot.org/uniprot/MDM4_HUMAN MDM4_HUMAN]] Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions.<ref>PMID:16163388</ref> <ref>PMID:16511572</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 28:		Line 28:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Grace, C R]]		[[Category: Grace, C R]]
	[[Category: Kriwacki, R W]]		[[Category: Kriwacki, R W]]
	[[Category: Mdmx]]		[[Category: Mdmx]]
	[[Category: Signaling protein]]		[[Category: Signaling protein]]

OCA at 17:18, 15 August 2018

OCA — Wed, 15 Aug 2018 17:18:06 GMT

←Older revision		Revision as of 17:18, 15 August 2018
Line 3:		Line 3:
	<StructureSection load='2n14' size='340' side='right' caption='[[2n14]], [[NMR_Ensembles_of_Models \| 20 NMR models]]' scene=''>		<StructureSection load='2n14' size='340' side='right' caption='[[2n14]], [[NMR_Ensembles_of_Models \| 20 NMR models]]' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[2n14]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N14 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2N14 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[2n14]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N14 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2N14 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=49H:4-({(4S,5R)-4-(3-CHLOROPHENYL)-5-(4-CHLOROPHENYL)-2-[4-METHOXY-2-(PROPAN-2-YLOXY)PHENYL]-4,5-DIHYDRO-1H-IMIDAZOL-1-YL}CARBONYL)PIPERAZIN-2-ONE'>49H</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=49H:4-({(4S,5R)-4-(3-CHLOROPHENYL)-5-(4-CHLOROPHENYL)-2-[4-METHOXY-2-(PROPAN-2-YLOXY)PHENYL]-4,5-DIHYDRO-1H-IMIDAZOL-1-YL}CARBONYL)PIPERAZIN-2-ONE'>49H</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2n0u\|2n0u]], [[2n0w\|2n0w]], [[2n06\|2n06]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2n0u\|2n0u]], [[2n0w\|2n0w]], [[2n06\|2n06]]</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=2n14 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n14 OCA], [http://pdbe.org/2n14 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2n14 RCSB], [http://www.ebi.ac.uk/pdbsum/2n14 PDBsum]</span></td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">MDM4, MDMX ([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=2n14 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n14 OCA], [http://pdbe.org/2n14 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2n14 RCSB], [http://www.ebi.ac.uk/pdbsum/2n14 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2n14 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 26:		Line 27:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Grace, C R]]		[[Category: Grace, C R]]
	[[Category: Kriwacki, R W]]		[[Category: Kriwacki, R W]]
	[[Category: Mdmx]]		[[Category: Mdmx]]
	[[Category: Signaling protein]]		[[Category: Signaling protein]]

OCA at 18:47, 10 May 2016

OCA — Tue, 10 May 2016 18:47:46 GMT

←Older revision		Revision as of 18:47, 10 May 2016
Line 1:		Line 1:
		+
	==Mdmx-295==		==Mdmx-295==
	<StructureSection load='2n14' size='340' side='right' caption='[[2n14]], [[NMR_Ensembles_of_Models \| 20 NMR models]]' scene=''>		<StructureSection load='2n14' size='340' side='right' caption='[[2n14]], [[NMR_Ensembles_of_Models \| 20 NMR models]]' scene=''>
Line 9:		Line 10:
	== Function ==		== Function ==
	[[http://www.uniprot.org/uniprot/MDM4_HUMAN MDM4_HUMAN]] Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions.<ref>PMID:16163388</ref> <ref>PMID:16511572</ref>		[[http://www.uniprot.org/uniprot/MDM4_HUMAN MDM4_HUMAN]] Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions.<ref>PMID:16163388</ref> <ref>PMID:16511572</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	While the gene for p53 is mutated in many human cancers causing loss of function, many others maintain a wild-type gene but exhibit reduced p53 tumor suppressor activity through overexpression of the negative regulators, Mdm2 and/or MdmX. For the latter mechanism of loss of function, the activity of endogenous p53 can be restored through inhibition of Mdm2 or MdmX with small molecules. We previously reported a series of compounds based upon the Nutlin-3 chemical scaffold that bind to both MdmX and Mdm2 [Vara, B. A. et al. (2014) Organocatalytic, diastereo- and enantioselective synthesis of nonsymmetric cis-stilbene diamines: A platform for the preparation of single-enantiomer cis-imidazolines for protein-protein inhibition. J. Org. Chem. 79, 6913-6938]. Here we present the first solution structures based on data from NMR spectroscopy for MdmX in complex with four of these compounds and compare them with the MdmX:p53 complex. A p53-derived peptide binds with high affinity (Kd value of 150nM) and causes the formation of an extensive network of hydrogen bonds within MdmX; this constitutes the induction of order within MdmX through ligand binding. In contrast, the compounds bind more weakly (Kd values from 600nM to 12muM) and induce an incomplete hydrogen bond network within MdmX. Despite relatively weak binding, the four compounds activated p53 and induced p21(Cip1) expression in retinoblastoma cell lines that overexpress MdmX, suggesting that they specifically target MdmX and/or Mdm2. Our results document structure-activity relationships for lead-like small molecules targeting MdmX and suggest a strategy for their further optimization in the future by using NMR spectroscopy to monitor small-molecule-induced protein order as manifested through hydrogen bond formation.
		+
		+	Monitoring Ligand-Induced Protein Ordering in Drug Discovery.,Grace CR, Ban D, Min J, Mayasundari A, Min L, Finch KE, Griffiths L, Bharatham N, Bashford D, Kiplin Guy R, Dyer MA, Kriwacki RW J Mol Biol. 2016 Mar 27;428(6):1290-303. doi: 10.1016/j.jmb.2016.01.016. Epub, 2016 Jan 23. PMID:26812210<ref>PMID:26812210</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 2n14" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[MDM4\|MDM4]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 02:24, 28 January 2016

OCA — Thu, 28 Jan 2016 02:24:16 GMT

←Older revision		Revision as of 02:24, 28 January 2016
Line 1:		Line 1:
-	'''~~Unreleased structure~~'''	+	==Mdmx-295==
-		+	<StructureSection load='2n14' size='340' side='right' caption='[[2n14]], [[NMR_Ensembles_of_Models \| 20 NMR models]]' scene=''>
-	~~The entry~~ 2n14 is ~~ON HOLD until Paper Publication~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[2n14]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N14 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2N14 FirstGlance]. <br>
-	~~Authors~~: ~~Grace~~, C.R., ~~Kriwacki~~, R.W.	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=49H:4-({(4S,5R)-4-(3-CHLOROPHENYL)-5-(4-CHLOROPHENYL)-2-[4-METHOXY-2-(PROPAN-2-YLOXY)PHENYL]-4,5-DIHYDRO-1H-IMIDAZOL-1-YL}CARBONYL)PIPERAZIN-2-ONE'>49H</scene></td></tr>
-		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2n0u\|2n0u]], [[2n0w\|2n0w]], [[2n06\|2n06]]</td></tr>
-	~~Description~~: ~~Mdmx~~-~~295~~	+	<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=2n14 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n14 OCA], [http://pdbe.org/2n14 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2n14 RCSB], [http://www.ebi.ac.uk/pdbsum/2n14 PDBsum]</span></td></tr>
-	[[Category: ~~Unreleased Structures~~]]	+	</table>
-	[[Category: Kriwacki, R.W]]	+	== Function ==
-	[[Category: ~~Grace, C.R~~]]	+	[[http://www.uniprot.org/uniprot/MDM4_HUMAN MDM4_HUMAN]] Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions.<ref>PMID:16163388</ref> <ref>PMID:16511572</ref>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Grace, C R]]
		+	[[Category: Kriwacki, R W]]
		+	[[Category: Mdmx]]
		+	[[Category: Signaling protein]]

OCA at 07:15, 24 June 2015

OCA — Wed, 24 Jun 2015 07:15:48 GMT

←Older revision		Revision as of 07:15, 24 June 2015
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 2n14 is ON HOLD	+	The entry 2n14 is ON HOLD until Paper Publication

	Authors: Grace, C.R., Kriwacki, R.W.		Authors: Grace, C.R., Kriwacki, R.W.

OCA at 06:02, 8 April 2015

OCA — Wed, 08 Apr 2015 06:02:30 GMT

←Older revision		Revision as of 06:02, 8 April 2015
Line 3:		Line 3:
	The entry 2n14 is ON HOLD		The entry 2n14 is ON HOLD

-	Authors: Grace, C., Kriwacki, R.	+	Authors: Grace, C.R., Kriwacki, R.W.

-	Description: ~~MDMX~~-295	+	Description: Mdmx-295
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Kriwacki, R]]	+	[[Category: Kriwacki, R.W]]
-	[[Category: Grace, C]]	+	[[Category: Grace, C.R]]

OCA: Protected "2n14" [edit=sysop:move=sysop]

OCA — Wed, 01 Apr 2015 07:46:15 GMT

Protected "2n14" [edit=sysop:move=sysop]

←Older revision

Revision as of 07:46, 1 April 2015

OCA: New page: '''Unreleased structure''' The entry 2n14 is ON HOLD Authors: Grace, C., Kriwacki, R. Description: MDMX-295 Category: Unreleased Structures Category: Kriwacki, R [[Category: Gr...

OCA — Wed, 01 Apr 2015 07:46:13 GMT

New page: '''Unreleased structure''' The entry 2n14 is ON HOLD Authors: Grace, C., Kriwacki, R. Description: MDMX-295 Category: Unreleased Structures Category: Kriwacki, R [[Category: Gr...

New page

'''Unreleased structure'''

The entry 2n14 is ON HOLD

Authors: Grace, C., Kriwacki, R.

Description: MDMX-295
[[Category: Unreleased Structures]]
[[Category: Kriwacki, R]]
[[Category: Grace, C]]