4wt2
From Proteopedia
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| - | ''' | + | ==Co-crystal Structure of MDM2 in Complex with AM-7209== |
| + | <StructureSection load='4wt2' size='340' side='right' caption='[[4wt2]], [[Resolution|resolution]] 1.42Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4wt2]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WT2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WT2 FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3UD:4-({[(3R,5R,6S)-1-[(1S)-2-(TERT-BUTYLSULFONYL)-1-CYCLOPROPYLETHYL]-6-(4-CHLORO-3-FLUOROPHENYL)-5-(3-CHLOROPHENYL)-3-METHYL-2-OXOPIPERIDIN-3-YL]ACETYL}AMINO)-2-METHOXYBENZOIC+ACID'>3UD</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=4wt2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wt2 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4wt2 RCSB], [http://www.ebi.ac.uk/pdbsum/4wt2 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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Structure-based rational design and extensive SAR led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with an 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition = 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo anti-tumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED50 = 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1. | ||
| - | + | Discovery of AM-7209, a Potent and Selective 4-Amidobenzoic Acid Inhibitor of the MDM2-p53 Interaction.,Rew Y, Sun D, Yan X, Beck HP, Canon J, Ada C, Duquette J, Eksterowicz J, Fox BM, Fu J, Gonzalez AZ, Houze JB, Huang X, Jiang B, Jin L, Li Y, Li Z, Ling Y, Lo MC, Long AM, McGee LR, McIntosh J, Oliner J, Osgood T, Saiki A, Shaffer P, Wortman S, Yakowec P, Ye Q, Yu D, Medina JC, Olson SH J Med Chem. 2014 Nov 10. PMID:25384157<ref>PMID:25384157</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | == References == | |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Huang, X]] | ||
| + | [[Category: Long, A M]] | ||
| + | [[Category: Shaffer, P L]] | ||
| + | [[Category: Yakowec, P]] | ||
| + | [[Category: Ligase-ligase inhibitor complex]] | ||
| + | [[Category: P53]] | ||
| + | [[Category: Protein-protein interaction]] | ||
Revision as of 09:31, 3 December 2014
Co-crystal Structure of MDM2 in Complex with AM-7209
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