6h22

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'''Unreleased structure'''
 
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The entry 6h22 is ON HOLD
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==Crystal structure of Mdm2 bound to a stapled peptide==
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<StructureSection load='6h22' size='340' side='right'caption='[[6h22]], [[Resolution|resolution]] 2.01&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6h22]] 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=6H22 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6H22 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FL5:12-(dimethylamino)-3,10-diethyl-N,N,N-trimethyl-3,10-dihydrodibenzo[3,4 7,8]cycloocta[1,2-d 5,6-d]bis([1,2,3]triazole)-5-aminium'>FL5</scene></td></tr>
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<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr>
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<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>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/RING-type_E3_ubiquitin_transferase RING-type E3 ubiquitin transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.2.27 2.3.2.27] </span></td></tr>
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<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=6h22 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6h22 OCA], [http://pdbe.org/6h22 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6h22 RCSB], [http://www.ebi.ac.uk/pdbsum/6h22 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6h22 ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[[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.
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== Function ==
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[[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The Sondheimer dialkyne is extensively used in double strain-promoted azide-alkyne cycloadditions. This reagent suffers with poor water-solubility and rapidly decomposes in aqueous solutions. This intrinsically limits its application in biological systems, and no effective solutions are currently available. Herein, we report the development of novel highly water-soluble, stable, and azide-reactive strained dialkyne reagents. To demonstrate their extensive utility, we applied our novel dialkynes to a double strain-promoted macrocyclisation strategy to generate functionalised p53-based stapled peptides for inhibiting the oncogenic p53-MDM2 interaction. These functionalised stapled peptides bind MDM2 with low nanomolar affinity and show p53 activation in a cellular environment. Overall, our highly soluble, stable and azide-reactive dialkynes offer significant advantages over the currently used Sondheimer dialkyne, and could be utilised for numerous biological applications.
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Authors: Wang, X., Sharma, K., Spring, D.R., Hyvonen, M.
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Water-soluble, stable and azide-reactive strained dialkynes for biocompatible double strain-promoted click chemistry.,Sharma K, Strizhak AV, Fowler E, Wang X, Xu W, Hatt Jensen C, Wu Y, Sore HF, Lau YH, Hyvonen M, Itzhaki LS, Spring DR Org Biomol Chem. 2019 Aug 16. doi: 10.1039/c9ob01745c. PMID:31418442<ref>PMID:31418442</ref>
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Description: Crystal structure of Mdm2 bound to a stapled peptide
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Spring, D.R]]
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<div class="pdbe-citations 6h22" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Human]]
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[[Category: Large Structures]]
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[[Category: RING-type E3 ubiquitin transferase]]
[[Category: Hyvonen, M]]
[[Category: Hyvonen, M]]
[[Category: Sharma, K]]
[[Category: Sharma, K]]
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[[Category: Spring, D R]]
[[Category: Wang, X]]
[[Category: Wang, X]]
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[[Category: E3-ligase]]
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[[Category: Inhibitor]]
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[[Category: Ligase]]
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[[Category: Stapled peptide]]

Current revision

Crystal structure of Mdm2 bound to a stapled peptide

PDB ID 6h22

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