3eqy: Difference between revisions

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-{{STRUCTURE_3eqy|  PDB=3eqy  |  SCENE=  }}
+==Crystal structure of human MDMX in complex with a 12-mer peptide inhibitor==
-===Crystal structure of human MDMX in complex with a 12-mer peptide inhibitor===
+<StructureSection load='3eqy' size='340' side='right' caption='[[3eqy]], [[Resolution|resolution]] 1.63&Aring;' scene=''>
-{{ABSTRACT_PUBMED_19255450}}
+== Structural highlights ==
+<table><tr><td colspan='2'>[[3eqy]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3EQY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3EQY FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GAI:GUANIDINE'>GAI</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3eqs|3eqs]], [[3dab|3dab]], [[3dac|3dac]], [[2z5t|2z5t]], [[2z5s|2z5s]]</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=3eqy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3eqy OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3eqy RCSB], [http://www.ebi.ac.uk/pdbsum/3eqy PDBsum]</span></td></tr>
+</table>
+== Function ==
+[[http://www.uniprot.org/uniprot/MDM4_HUMAN MDM4_HUMAN]] Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions.<ref>PMID:16163388</ref> <ref>PMID:16511572</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/eq/3eqy_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/chain_selection.php?pdb_ID=2ata ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The oncoproteins MDM2 and MDMX negatively regulate the activity and stability of the tumor suppressor protein p53-a cellular process initiated by MDM2 and/or MDMX binding to the N-terminal transactivation domain of p53. MDM2 and MDMX in many tumors confer p53 inactivation and tumor survival, and are important molecular targets for anticancer therapy. We screened a duodecimal peptide phage library against site-specifically biotinylated p53-binding domains of human MDM2 and MDMX chemically synthesized via native chemical ligation, and identified several peptide inhibitors of the p53-MDM2/MDMX interactions. The most potent inhibitor (TSFAEYWNLLSP), termed PMI, bound to MDM2 and MDMX at low nanomolar affinities-approximately 2 orders of magnitude stronger than the wild-type p53 peptide of the same length (ETFSDLWKLLPE). We solved the crystal structures of synthetic MDM2 and MDMX, both in complex with PMI, at 1.6 A resolution. Comparative structural analysis identified an extensive, tightened intramolecular H-bonding network in bound PMI that contributed to its conformational stability, thus enhanced binding to the 2 oncogenic proteins. Importantly, the C-terminal residue Pro of PMI induced formation of a hydrophobic cleft in MDMX previously unseen in the structures of p53-bound MDM2 or MDMX. Our findings deciphered the structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX, shedding new light on structure-based rational design of different classes of p53 activators for potential therapeutic use.
-==Function==
+Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX.,Pazgier M, Liu M, Zou G, Yuan W, Li C, Li C, Li J, Monbo J, Zella D, Tarasov SG, Lu W Proc Natl Acad Sci U S A. 2009 Mar 2. PMID:19255450<ref>PMID:19255450</ref>
-[[http://www.uniprot.org/uniprot/MDM4_HUMAN MDM4_HUMAN]] Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions.<ref>PMID:16163388</ref> <ref>PMID:16511572</ref>
-==About this Structure==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[3eqy]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3EQY OCA].
+</div>
 ==See Also==
 *[[MDM4|MDM4]]
+== References ==
-==Reference==
+<references/>
-<ref group="xtra">PMID:019255450</ref><references group="xtra"/><references/>
+__TOC__
-[[Category: Lu, W.]]
+</StructureSection>
-[[Category: Pazgier, M.]]
+[[Category: Lu, W]]
+[[Category: Pazgier, M]]
 [[Category: Mdm4]]
 [[Category: Mdmx]]