3jzr: Difference between revisions

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-{{Seed}}
-[[Image:3jzr.png|left|200px]]
-<!--
+==Human MDM2 liganded with a 12mer peptide inhibitor (pDI6W)==
-The line below this paragraph, containing "STRUCTURE_3jzr", creates the "Structure Box" on the page.
+<StructureSection load='3jzr' size='340' side='right'caption='[[3jzr]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
+== Structural highlights ==
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+<table><tr><td colspan='2'>[[3jzr]] 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=3JZR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3JZR FirstGlance]. <br>
-or leave the SCENE parameter empty for the default display.
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1&#8491;</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=3jzr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3jzr OCA], [https://pdbe.org/3jzr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3jzr RCSB], [https://www.ebi.ac.uk/pdbsum/3jzr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3jzr ProSAT]</span></td></tr>
-{{STRUCTURE_3jzr|  PDB=3jzr  |  SCENE=  }}
+</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>
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/jz/3jzr_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3jzr ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+MDM2 and MDMX function as key regulators of p53 by binding to its N terminus, inhibiting its transcriptional activity, and promoting degradation. MDM2 and MDMX overexpression or hyperactivation directly contributes to the loss of p53 function during the development of nearly 50% of human cancers. Recent studies showed that disrupting p53-MDM2 and p53-MDMX interactions can lead to robust activation of p53 but also revealed a need to develop novel dual specific or MDMX-specific inhibitors. Using phage display we identified a 12-residue peptide (pDI) with inhibitory activity against MDM2 and MDMX. The co-crystal structures of the pDI and a single mutant derivative (pDI6W) liganded with the N-terminal domains of human MDMX and MDM2 served as the basis for the design of 11 distinct pDI-derivative peptides that were tested for inhibitory potential. The best derivative (termed pDIQ) contained four amino acid substitutions and exhibited a 5-fold increase in potency over the parent peptide against both MDM2 (IC(50) = 8 nm) and MDMX (IC(50) = 110 nm). Further structural studies revealed key molecular features enabling the high affinity binding of the pDIQ to these proteins. These include large conformational changes of the pDIQ to reach into a hydrophobic site unique to MDMX. The findings suggest new strategies toward the rational design of small molecule inhibitors efficiently targeting MDMX.
-===Human MDM2 liganded with a 12mer peptide inhibitor (pDI6W)===
+Structure-based design of high affinity peptides inhibiting the interaction of p53 with MDM2 and MDMX.,Phan J, Li Z, Kasprzak A, Li B, Sebti S, Guida W, Schonbrunn E, Chen J J Biol Chem. 2010 Jan 15;285(3):2174-83. Epub 2009 Nov 12. PMID:19910468<ref>PMID:19910468</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 3jzr" style="background-color:#fffaf0;"></div>
-<!--
+==See Also==
-The line below this paragraph, {{ABSTRACT_PUBMED_19910468}}, adds the Publication Abstract to the page
+*[[MDM2 3D structures|MDM2 3D structures]]
-(as it appears on PubMed at http://www.pubmed.gov), where 19910468 is the PubMed ID number.
+== References ==
--->
+<references/>
-{{ABSTRACT_PUBMED_19910468}}
+__TOC__
+</StructureSection>
-==About this Structure==
-JZR is a 2 chains structure of sequences 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=3JZR OCA].
-==Reference==
-<ref group="xtra">PMID:19910468</ref><references group="xtra"/>
 [[Category: Homo sapiens]]
-[[Category: Phan, J.]]
+[[Category: Large Structures]]
-[[Category: Schonbrunn, E.]]
+[[Category: Phan J]]
-[[Category: Alternative splicing]]
+[[Category: Schonbrunn E]]
-[[Category: Cytoplasm]]
-[[Category: Double minute 2 protein]]
-[[Category: Hdm2]]
-[[Category: Host-virus interaction]]
-[[Category: Ligase]]
-[[Category: Metal-binding]]
-[[Category: Nucleus]]
-[[Category: Oncoprotein mdm2]]
-[[Category: P53-binding protein mdm2]]
-[[Category: Phosphoprotein]]
-[[Category: Proto-oncogene]]
-[[Category: Ubl conjugation]]
-[[Category: Ubl conjugation pathway]]
-[[Category: Zinc]]
-[[Category: Zinc-finger]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Dec  2 09:26:14 2009''