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| | <StructureSection load='5vk1' size='340' side='right'caption='[[5vk1]], [[Resolution|resolution]] 2.69Å' scene=''> | | <StructureSection load='5vk1' size='340' side='right'caption='[[5vk1]], [[Resolution|resolution]] 2.69Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5vk1]] is a 16 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VK1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5VK1 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5vk1]] is a 16 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VK1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5VK1 FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=9E7:'>9E7</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.69Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3eqy|3eqy]], [[5vk0|5vk0]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9E7:N~6~-(sulfanylmethyl)-L-lysine'>9E7</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></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=5vk1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vk1 OCA], [http://pdbe.org/5vk1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5vk1 RCSB], [http://www.ebi.ac.uk/pdbsum/5vk1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5vk1 ProSAT]</span></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=5vk1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vk1 OCA], [https://pdbe.org/5vk1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5vk1 RCSB], [https://www.ebi.ac.uk/pdbsum/5vk1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5vk1 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == 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> | + | [https://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> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Gohain, N]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Pazgier, M]] | + | [[Category: Gohain N]] |
| - | [[Category: Tolbert, W D]] | + | [[Category: Pazgier M]] |
| - | [[Category: Mdmx]] | + | [[Category: Tolbert WD]] |
| - | [[Category: Mdmx-peptide inhibitor complex]]
| + | |
| - | [[Category: Metal-binding]]
| + | |
| - | [[Category: Nucleus]]
| + | |
| - | [[Category: Oncoprotein]]
| + | |
| - | [[Category: Signaling protein-inhibitor complex]]
| + | |
| - | [[Category: Stapled peptide]]
| + | |
| - | [[Category: Zinc-finger]]
| + | |
| Structural highlights
Function
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.[1] [2]
Publication Abstract from PubMed
Two major pharmacological hurdles severely limit the widespread use of small peptides as therapeutics: poor proteolytic stability and membrane permeability. Importantly, low aqueous solubility also impedes the development of peptides for clinical use. Various elaborate side chain stapling chemistries have been developed for alpha-helical peptides to circumvent this problem, with considerable success in spite of inevitable limitations. Here we report a novel peptide stapling strategy based on the dithiocarbamate chemistry linking the side chains of residues Lys(i) and Cys(i + 4) of unprotected peptides and apply it to a series of dodecameric peptide antagonists of the p53-inhibitory oncogenic proteins MDM2 and MDMX. Crystallographic studies of peptide-MDM2/MDMX complexes structurally validated the chemoselectivity of the dithiocarbamate staple bridging Lys and Cys at (i, i + 4) positions. One dithiocarbamate-stapled PMI derivative, (DTC)PMI, showed a 50-fold stronger binding to MDM2 and MDMX than its linear counterpart. Importantly, in contrast to PMI and its linear derivatives, the (DTC)PMI peptide actively traversed the cell membrane and killed HCT116 tumor cells in vitro by activating the tumor suppressor protein p53. Compared with other known stapling techniques, our solution-based DTC stapling chemistry is simple, cost-effective, regio-specific and environmentally friendly, promising an important new tool for the development of peptide therapeutics with improved pharmacological properties including aqueous solubility, proteolytic stability and membrane permeability.
Dithiocarbamate-inspired side chain stapling chemistry for peptide drug design.,Li X, Tolbert WD, Hu HG, Gohain N, Zou Y, Niu F, He WX, Yuan W, Su JC, Pazgier M, Lu W Chem Sci. 2018 Nov 30;10(5):1522-1530. doi: 10.1039/c8sc03275k. eCollection 2019 , Feb 7. PMID:30809370[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Chen L, Gilkes DM, Pan Y, Lane WS, Chen J. ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage. EMBO J. 2005 Oct 5;24(19):3411-22. Epub 2005 Sep 15. PMID:16163388 doi:10.1038/sj.emboj.7600812
- ↑ Jin Y, Dai MS, Lu SZ, Xu Y, Luo Z, Zhao Y, Lu H. 14-3-3gamma binds to MDMX that is phosphorylated by UV-activated Chk1, resulting in p53 activation. EMBO J. 2006 Mar 22;25(6):1207-18. Epub 2006 Mar 2. PMID:16511572 doi:10.1038/sj.emboj.7601010
- ↑ Li X, Tolbert WD, Hu HG, Gohain N, Zou Y, Niu F, He WX, Yuan W, Su JC, Pazgier M, Lu W. Dithiocarbamate-inspired side chain stapling chemistry for peptide drug design. Chem Sci. 2018 Nov 30;10(5):1522-1530. doi: 10.1039/c8sc03275k. eCollection 2019 , Feb 7. PMID:30809370 doi:http://dx.doi.org/10.1039/c8sc03275k
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