3vzv
From Proteopedia
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| - | [[ | + | ==Crystal structure of human mdm2 with a dihydroimidazothiazole inhibitor== |
| + | <StructureSection load='3vzv' size='340' side='right' caption='[[3vzv]], [[Resolution|resolution]] 2.80Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[3vzv]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3VZV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3VZV FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=VZV:1-{[(5R,6S)-5,6-BIS(4-CHLOROPHENYL)-6-METHYL-3-(PROPAN-2-YL)-5,6-DIHYDROIMIDAZO[2,1-B][1,3]THIAZOL-2-YL]CARBONYL}-N,N-DIMETHYL-L-PROLINAMIDE'>VZV</scene></td></tr> | ||
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MDM2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=3vzv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3vzv OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3vzv RCSB], [http://www.ebi.ac.uk/pdbsum/3vzv 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 == | ||
| + | With the aim of discovering potent inhibitors of the p53-MDM2 interaction and thus obtaining a potent anticancer drug, we have pursued synthesis and optimization of dihydroimidazothiazole derivatives, which have been discovered via scaffold hopping by mimicing the mode of interaction between MDM2 and Nutlins. Upon the discovery we encountered a problem involving the chemical instability of the scaffold, that is, susceptibility to oxidation which led to imidazothiazole. In order to solve this problem and to obtain further potent compounds, we executed medicinal research and thus furnished the optimal compounds by incorporating the methyl group onto the C-6 position to avoid the oxidation, and by modifying the C-2 moiety of the additional proline motif, which furnished high potency. The incorporation of the pyrrolidine moiety at the C-2 position raised another hydrophobic interaction site with MDM2 protein, which was generated by the induced-fitting observed by co-crystal structure analysis. These optimal molecules showed significant improvement in potency when compared with the early lead (+)-1 or Nutlin-3a. | ||
| - | + | Lead optimization of novel p53-MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold.,Miyazaki M, Naito H, Sugimoto Y, Kawato H, Okayama T, Shimizu H, Miyazaki M, Kitagawa M, Seki T, Fukutake S, Aonuma M, Soga T Bioorg Med Chem Lett. 2013 Feb 1;23(3):728-32. doi: 10.1016/j.bmcl.2012.11.091., Epub 2012 Dec 1. PMID:23266121<ref>PMID:23266121</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| + | </div> | ||
| - | + | ==See Also== | |
| - | + | *[[MDM2|MDM2]] | |
| - | == | + | == References == |
| - | [[ | + | <references/> |
| + | __TOC__ | ||
| + | </StructureSection> | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
| - | [[Category: Katakura, S | + | [[Category: Katakura, S]] |
| - | [[Category: Kawato, H | + | [[Category: Kawato, H]] |
| - | [[Category: Miyazaki, M | + | [[Category: Miyazaki, M]] |
| - | [[Category: Naito, H | + | [[Category: Naito, H]] |
| - | [[Category: Okayama, T | + | [[Category: Okayama, T]] |
| - | [[Category: Shimizu, H | + | [[Category: Shimizu, H]] |
| - | [[Category: Soga, T | + | [[Category: Soga, T]] |
| - | [[Category: Sugimoto, Y | + | [[Category: Sugimoto, Y]] |
[[Category: Ligase-ligase inhibitor complex]] | [[Category: Ligase-ligase inhibitor complex]] | ||
[[Category: P53]] | [[Category: P53]] | ||
[[Category: Ubiquitin-protein ligase e3 mdm2]] | [[Category: Ubiquitin-protein ligase e3 mdm2]] | ||
Revision as of 19:39, 25 December 2014
Crystal structure of human mdm2 with a dihydroimidazothiazole inhibitor
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