3v3b: Difference between revisions
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==Structure of the Stapled p53 Peptide Bound to Mdm2== | |||
<StructureSection load='3v3b' size='340' side='right' caption='[[3v3b]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3v3b]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3V3B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3V3B FirstGlance]. <br> | |||
==Disease== | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr> | ||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=0EH:(2R)-2-AMINO-2-METHYLNONANOIC+ACID'>0EH</scene>, <scene name='pdbligand=MK8:2-METHYL-L-NORLEUCINE'>MK8</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1ycr|1ycr]]</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 HUMAN])</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=3v3b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3v3b OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3v3b RCSB], [http://www.ebi.ac.uk/pdbsum/3v3b 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. | [[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 == | |||
Mdm2 is a major negative regulator of the tumor suppressor p53 protein, a protein that plays a crucial role in maintaining genome integrity. Inactivation of p53 is the most prevalent defect in human cancers. Inhibitors of the Mdm2-p53 interaction that restore the functional p53 constitute potential nongenotoxic anticancer agents with a novel mode of action. We present here a 2.0 A resolution structure of the Mdm2 protein with a bound stapled p53 peptide. Such peptides, which are conformationally and proteolytically stabilized with all-hydrocarbon staples, are an emerging class of biologics that are capable of disrupting protein-protein interactions and thus have broad therapeutic potential. The structure represents the first crystal structure of an i, i + 7 stapled peptide bound to its target and reveals that rather than acting solely as a passive conformational brace, a staple can intimately interact with the surface of a protein and augment the binding interface. | |||
Structure of the Stapled p53 Peptide Bound to Mdm2.,Baek S, Kutchukian PS, Verdine GL, Huber R, Holak TA, Lee KW, Popowicz GM J Am Chem Soc. 2012 Jan 11;134(1):103-6. Epub 2011 Dec 14. PMID:22148351<ref>PMID:22148351</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[MDM2|MDM2]] | *[[MDM2|MDM2]] | ||
== References == | |||
== | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Human]] | [[Category: Human]] | ||
[[Category: Baek, S | [[Category: Baek, S]] | ||
[[Category: Holak, T A | [[Category: Holak, T A]] | ||
[[Category: Huber, R | [[Category: Huber, R]] | ||
[[Category: Kutchukian, P S | [[Category: Kutchukian, P S]] | ||
[[Category: Popowicz, G M | [[Category: Popowicz, G M]] | ||
[[Category: Verdine, G L | [[Category: Verdine, G L]] | ||
[[Category: Won, L Ki | [[Category: Won, L Ki]] | ||
[[Category: Aliphatic staple]] | [[Category: Aliphatic staple]] | ||
[[Category: Cancer]] | [[Category: Cancer]] | ||
