4qoc

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Current revision (12:47, 1 March 2024) (edit) (undo)
 
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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4qoc]] is a 6 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=4QOC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QOC FirstGlance]. <br>
<table><tr><td colspan='2'>[[4qoc]] is a 6 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=4QOC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QOC FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=35T:{(3R,5R,6S)-5-(3-CHLOROPHENYL)-6-(4-CHLOROPHENYL)-1-[(1S)-1-CYCLOPROPYL-2-(PYRROLIDIN-1-YLSULFONYL)ETHYL]-3-METHYL-2-OXOPIPERIDIN-3-YL}ACETIC+ACID'>35T</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=35T:{(3R,5R,6S)-5-(3-CHLOROPHENYL)-6-(4-CHLOROPHENYL)-1-[(1S)-1-CYCLOPROPYL-2-(PYRROLIDIN-1-YLSULFONYL)ETHYL]-3-METHYL-2-OXOPIPERIDIN-3-YL}ACETIC+ACID'>35T</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=4qoc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qoc OCA], [https://pdbe.org/4qoc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qoc RCSB], [https://www.ebi.ac.uk/pdbsum/4qoc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qoc 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=4qoc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qoc OCA], [https://pdbe.org/4qoc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qoc RCSB], [https://www.ebi.ac.uk/pdbsum/4qoc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qoc ProSAT]</span></td></tr>
</table>
</table>
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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>
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<div style="background-color:#fffaf0;">
 
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== Publication Abstract from PubMed ==
 
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We recently reported on the discovery of AMG 232, a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. AMG 232 is being evaluated in human clinical trials for cancer. Continued exploration of the N-alkyl substituent of this series, in an effort to optimize interactions with the MDM2 glycine-58 shelf region, led to the discovery of sulfonamides such as compounds 31 and 38 that have similar potency, hepatocyte stability and rat pharmacokinetic properties to AMG 232.
 
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Optimization beyond AMG 232: discovery and SAR of sulfonamides on a piperidinone scaffold as potent inhibitors of the MDM2-p53 protein-protein interaction.,Wang Y, Zhu J, Liu JJ, Chen X, Mihalic J, Deignan J, Yu M, Sun D, Kayser F, McGee LR, Lo MC, Chen A, Zhou J, Ye Q, Huang X, Long AM, Yakowec P, Oliner JD, Olson SH, Medina JC Bioorg Med Chem Lett. 2014 Aug 15;24(16):3782-5. doi: 10.1016/j.bmcl.2014.06.073., Epub 2014 Jul 1. PMID:25042256<ref>PMID:25042256</ref>
 
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 
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</div>
 
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<div class="pdbe-citations 4qoc" style="background-color:#fffaf0;"></div>
 
==See Also==
==See Also==

Current revision

crystal structure of compound 16 bound to MDM2(17-111), {(3R,5R,6S)-5-(3-CHLOROPHENYL)-6-(4-CHLOROPHENYL)-1-[(1S)-1-CYCLOPROPYL-2-(PYRROLIDIN-1-YLSULFONYL)ETHYL]-3-METHYL-2-OXOPIPERIDIN-3-YL}ACETIC ACID

PDB ID 4qoc

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OCA

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