4zfi: Difference between revisions

← Older edit

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 4zfi is ON HOLD  until Apr 21 2017
+==Structure of Mdm2 with low molecular weight inhibitor==
+<StructureSection load='4zfi' size='340' side='right'caption='[[4zfi]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4zfi]] 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=4ZFI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZFI 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&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4NJ:(5S)-3,5-BIS(4-CHLOROBENZYL)-4-(6-CHLORO-1H-INDOL-3-YL)-5-HYDROXY-1-METHYL-1,5-DIHYDRO-2H-PYRROL-2-ONE'>4NJ</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=4zfi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zfi OCA], [https://pdbe.org/4zfi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zfi RCSB], [https://www.ebi.ac.uk/pdbsum/4zfi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zfi 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 ==
+The p53 pathway is inactivated in almost all types of cancer by mutations in the p53 encoding gene or overexpression of the p53 negative regulators, Mdm2 and/or Mdmx. Restoration of the p53 function by inhibition of the p53-Mdm2/Mdmx interaction opens up a prospect for a non-genotoxic anticancer therapy. Here we present the syntheses, activities and crystal structures on two novel classes of Mdm2-p53 inhibitors that are based on the 3-pyrrolin-2-one and 2-furanone scaffolds. The structures of the complexes formed by these inhibitors and Mdm2 reveal the dimeric protein molecular organization that has not been observed in the small-molecule/Mdm2 complexes described until now. In particular, the 6-chloroindole group does not occupy the usual Trp-23 pocket of Mdm2, but instead is engaged in dimerization. This entirely unique binding mode of the compounds opens new possibilities for optimization of the Mdm2-p53 interaction inhibitors.
-Authors: Wrona, E.M., Twarda, A., Zak, K.M., Tomala, M., Grudnik, P., Krzemien, D., Jablonski, M., Kalinowska-Tluscik, J., Domling, A., Dubin, G., Holak, T.A.
+A Unique Mdm2-Binding Mode of the 3-Pyrrolin-2-one- and 2-Furanone-Based Antagonists of the p53-Mdm2 Interaction.,Surmiak E, Twarda-Clapa A, Zak KM, Musielak B, Tomala MD, Kubica K, Grudnik P, Madej M, Jablonski M, Potempa J, Kalinowska-Tluscik J, Dubin G, Domling A, Holak TA ACS Chem Biol. 2016 Oct 6. PMID:27709883<ref>PMID:27709883</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Grudnik, P]]
+<div class="pdbe-citations 4zfi" style="background-color:#fffaf0;"></div>
-[[Category: Kalinowska-Tluscik, J]]
-[[Category: Domling, A]]
+==See Also==
-[[Category: Jablonski, M]]
+*[[MDM2 3D structures|MDM2 3D structures]]
-[[Category: Zak, K.M]]
+== References ==
-[[Category: Krzemien, D]]
+<references/>
-[[Category: Wrona, E.M]]
+__TOC__
-[[Category: Holak, T.A]]
+</StructureSection>
-[[Category: Twarda, A]]
+[[Category: Homo sapiens]]
-[[Category: Dubin, G]]
+[[Category: Large Structures]]
-[[Category: Tomala, M]]
+[[Category: Dubin G]]
+[[Category: Grudnik P]]
+[[Category: Holak TA]]
+[[Category: Twarda-Clapa A]]
+[[Category: Wrona EM]]
+[[Category: Zak KM]]