3lnz

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[[Image:3lnz.png|left|200px]]
 
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{{STRUCTURE_3lnz| PDB=3lnz | SCENE= }}
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==Crystal structure of human MDM2 with a 12-mer peptide inhibitor PMI (N8A mutant)==
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<StructureSection load='3lnz' size='340' side='right'caption='[[3lnz]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3lnz]] is a 16 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=3LNZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3LNZ FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3lnz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3lnz OCA], [https://pdbe.org/3lnz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3lnz RCSB], [https://www.ebi.ac.uk/pdbsum/3lnz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3lnz ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[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.
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== Function ==
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[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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ln/3lnz_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=3lnz ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Inhibition of the interaction between the tumor suppressor protein p53 and its negative regulators MDM2 and MDMX is of great interest in cancer biology and drug design. We previously reported a potent duodecimal peptide inhibitor, termed PMI (TSFAEYWNLLSP), of the p53-MDM2 and -MDMX interactions. PMI competes with p53 for MDM2 and MDMX binding at an affinity roughly 2 orders of magnitude higher than that of (17-28)p53 (ETFSDLWKLLPE) of the same length; both peptides adopt nearly identical alpha-helical conformations in the complexes, where the three highlighted hydrophobic residues Phe, Trp, and Leu dominate PMI or (17-28)p53 binding to MDM2 and MDMX. To elucidate the molecular determinants for PMI activity and specificity, we performed a systematic Ala scanning mutational analysis of PMI and (17-28)p53. The binding affinities for MDM2 and MDMX of a total of 35 peptides including 10 truncation analogs were quantified, affording a complete dissection of energetic contributions of individual residues of PMI and (17-28)p53 to MDM2 and MDMX association. Importantly, the N8A mutation turned PMI into the most potent dual-specific antagonist of MDM2 and MDMX reported to date, registering respective K(d) values of 490 pM and 2.4 nM. The co-crystal structure of N8A-PMI-(25-109)MDM2 was determined at 1.95 A, affirming that high-affinity peptide binding to MDM2/MDMX necessitates, in addition to optimized intermolecular interactions, enhanced helix stability or propensity contributed by non-contact residues. The powerful empirical binding data and crystal structures present a unique opportunity for computational studies of peptide inhibition of the p53-MDM2/MDMX interactions.
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===Crystal structure of human MDM2 with a 12-mer peptide inhibitor PMI (N8A mutant)===
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Systematic mutational analysis of peptide inhibition of the p53-MDM2/MDMX interactions.,Li C, Pazgier M, Li C, Yuan W, Liu M, Wei G, Lu WY, Lu W J Mol Biol. 2010 Apr 30;398(2):200-13. Epub 2010 Mar 10. PMID:20226197<ref>PMID:20226197</ref>
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{{ABSTRACT_PUBMED_20226197}}
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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==About this Structure==
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<div class="pdbe-citations 3lnz" style="background-color:#fffaf0;"></div>
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[[3lnz]] is a 16 chain structure of [[MDM2]]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3LNZ OCA].
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==See Also==
==See Also==
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*[[MDM2|MDM2]]
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*[[MDM2 3D structures|MDM2 3D structures]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:020226197</ref><references group="xtra"/>
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__TOC__
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[[Category: Lu, W.]]
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</StructureSection>
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[[Category: Pazgier, M.]]
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[[Category: Homo sapiens]]
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[[Category: Hdm2]]
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[[Category: Large Structures]]
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[[Category: Host-virus interaction]]
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[[Category: Lu W]]
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[[Category: Human double minute 2 protein]]
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[[Category: Pazgier M]]
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[[Category: Ligase]]
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[[Category: Ligase-ligase inhibitor complex]]
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[[Category: Mdm2-peptide inhibitor complex]]
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[[Category: Metal-binding]]
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[[Category: Nucleus]]
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[[Category: Oncoprotein mdm2]]
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[[Category: P53 peptide activator n8a-pmi]]
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[[Category: P53-binding protein of mdm2]]
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[[Category: Phosphoprotein]]
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[[Category: Proto-oncogene]]
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[[Category: Ubl conjugation pathway]]
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[[Category: Zinc-finger]]
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Current revision

Crystal structure of human MDM2 with a 12-mer peptide inhibitor PMI (N8A mutant)

PDB ID 3lnz

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