4oq3
From Proteopedia
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| - | {{STRUCTURE_4oq3| PDB=4oq3 | SCENE= }} | ||
| - | ===Tetra-substituted imidazoles as a new class of inhibitors of the p53-MDM2 interaction=== | ||
| - | {{ABSTRACT_PUBMED_24704029}} | ||
| - | == | + | ==Tetra-substituted imidazoles as a new class of inhibitors of the p53-MDM2 interaction== |
| - | [[http://www.uniprot.org/uniprot/MDM2_HUMAN MDM2_HUMAN | + | <StructureSection load='4oq3' size='340' side='right'caption='[[4oq3]], [[Resolution|resolution]] 2.30Å' scene=''> |
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4oq3]] is a 4 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=4OQ3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OQ3 FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2V8:1-(5-CHLORO-2-METHYLPHENYL)-5-(3-CHLOROPHENYL)-2-(3-METHYLPHENYL)-1H-IMIDAZOLE-4-CARBOXYLIC+ACID'>2V8</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=4oq3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4oq3 OCA], [https://pdbe.org/4oq3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4oq3 RCSB], [https://www.ebi.ac.uk/pdbsum/4oq3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4oq3 ProSAT]</span></td></tr> | ||
| + | </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 == | ||
| + | Capitalizing on crystal structure information obtained from a previous effort in the search for non peptide inhibitors of the p53-MDM2 interaction, we have discovered another new class of compounds able to disrupt this protein-protein interaction, an important target in oncology drug research. The new inhibitors, based on a tetra-substituted imidazole scaffold, have been optimized to low nanomolar potency in a biochemical assay following a structure-guided approach. An appropriate strategy has allowed us to translate the high biochemical potency in significant anti-proliferative activity on a p53-dependent MDM2 amplified cell line. | ||
| - | + | Tetra-substituted imidazoles as a new class of inhibitors of the p53-MDM2 interaction.,Vaupel A, Bold G, De Pover A, Stachyra-Valat T, Hergovich-Lisztwan J, Kallen J, Masuya K, Furet P Bioorg Med Chem Lett. 2014 May 1;24(9):2110-4. doi: 10.1016/j.bmcl.2014.03.039., Epub 2014 Mar 22. PMID:24704029<ref>PMID:24704029</ref> | |
| - | + | ||
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| + | <div class="pdbe-citations 4oq3" style="background-color:#fffaf0;"></div> | ||
| - | == | + | ==See Also== |
| - | + | *[[MDM2 3D structures|MDM2 3D structures]] | |
| - | [[Category: | + | == References == |
| - | [[Category: | + | <references/> |
| - | [[Category: | + | __TOC__ |
| - | + | </StructureSection> | |
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Kallen J]] | ||
Current revision
Tetra-substituted imidazoles as a new class of inhibitors of the p53-MDM2 interaction
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