4dij

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4dij]] is a 2 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=4DIJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DIJ FirstGlance]. <br>
<table><tr><td colspan='2'>[[4dij]] is a 2 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=4DIJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DIJ 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=BLF:6-CHLORO-3-[1-(4-CHLOROBENZYL)-4-PHENYL-1H-IMIDAZOL-5-YL]-N-[2-(MORPHOLIN-4-YL)ETHYL]-1H-INDOLE-2-CARBOXAMIDE'>BLF</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]] 1.9&#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=BLF:6-CHLORO-3-[1-(4-CHLOROBENZYL)-4-PHENYL-1H-IMIDAZOL-5-YL]-N-[2-(MORPHOLIN-4-YL)ETHYL]-1H-INDOLE-2-CARBOXAMIDE'>BLF</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=4dij FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dij OCA], [https://pdbe.org/4dij PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dij RCSB], [https://www.ebi.ac.uk/pdbsum/4dij PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dij 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=4dij FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dij OCA], [https://pdbe.org/4dij PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dij RCSB], [https://www.ebi.ac.uk/pdbsum/4dij PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dij ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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[[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.
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[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 ==
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[[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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[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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Disrupting the interaction between the p53 tumor suppressor and its regulator MDM2 is a promising therapeutic strategy in anticancer drug research. In our search for non peptide inhibitors of this protein-protein interaction, we have devised a ligand design concept exploiting the central position of Val 93 in the p53 binding pocket of MDM2. The design of molecules based on this concept has allowed us to rapidly identify compounds having a 3-imidazolyl indole core structure as the first representatives of a new class of potent inhibitors of the p53-MDM2 interaction.
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The central valine concept provides an entry in a new class of non peptide inhibitors of the p53-MDM2 interaction.,Furet P, Chene P, De Pover A, Valat TS, Lisztwan JH, Kallen J, Masuya K Bioorg Med Chem Lett. 2012 Mar 30. PMID:22507962<ref>PMID:22507962</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 4dij" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==

Current revision

The Central Valine Concept Provides an Entry in a New Class of Non Peptide Inhibitors of the P53-MDM2 Interaction

PDB ID 4dij

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Proteopedia Page Contributors and Editors (what is this?)

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