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| | ==Mdmx-298== | | ==Mdmx-298== |
| - | <StructureSection load='2n06' size='340' side='right'caption='[[2n06]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | + | <StructureSection load='2n06' size='340' side='right'caption='[[2n06]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2n06]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N06 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2N06 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2n06]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N06 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2N06 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=44Z:4-[[(4S,5R)-5-(4-CHLOROPHENYL)-4-(3-METHOXYPHENYL)-2-(4-METHOXY-2-PROPAN-2-YLOXY-PHENYL)-4,5-DIHYDROIMIDAZOL-1-YL]CARBONYL]PIPERAZIN-2-ONE'>44Z</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2mwy|2mwy]], [[2n0u|2n0u]], [[2n0w|2n0w]], [[2n14|2n14]]</div></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=44Z:4-[[(4S,5R)-5-(4-CHLOROPHENYL)-4-(3-METHOXYPHENYL)-2-(4-METHOXY-2-PROPAN-2-YLOXY-PHENYL)-4,5-DIHYDROIMIDAZOL-1-YL]CARBONYL]PIPERAZIN-2-ONE'>44Z</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MDM4, MDMX ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=2n06 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n06 OCA], [https://pdbe.org/2n06 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2n06 RCSB], [https://www.ebi.ac.uk/pdbsum/2n06 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2n06 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=2n06 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n06 OCA], [https://pdbe.org/2n06 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2n06 RCSB], [https://www.ebi.ac.uk/pdbsum/2n06 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2n06 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[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>
| + | [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: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Grace, C R]] | + | [[Category: Grace CR]] |
| - | [[Category: Kriwacki, R W]] | + | [[Category: Kriwacki RW]] |
| - | [[Category: Mdmx]]
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| - | [[Category: P53]]
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| - | [[Category: Signaling protein]]
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| 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
While the gene for p53 is mutated in many human cancers causing loss of function, many others maintain a wild-type gene but exhibit reduced p53 tumor suppressor activity through overexpression of the negative regulators, Mdm2 and/or MdmX. For the latter mechanism of loss of function, the activity of endogenous p53 can be restored through inhibition of Mdm2 or MdmX with small molecules. We previously reported a series of compounds based upon the Nutlin-3 chemical scaffold that bind to both MdmX and Mdm2 [Vara, B. A. et al. (2014) Organocatalytic, diastereo- and enantioselective synthesis of nonsymmetric cis-stilbene diamines: A platform for the preparation of single-enantiomer cis-imidazolines for protein-protein inhibition. J. Org. Chem. 79, 6913-6938]. Here we present the first solution structures based on data from NMR spectroscopy for MdmX in complex with four of these compounds and compare them with the MdmX:p53 complex. A p53-derived peptide binds with high affinity (Kd value of 150nM) and causes the formation of an extensive network of hydrogen bonds within MdmX; this constitutes the induction of order within MdmX through ligand binding. In contrast, the compounds bind more weakly (Kd values from 600nM to 12muM) and induce an incomplete hydrogen bond network within MdmX. Despite relatively weak binding, the four compounds activated p53 and induced p21(Cip1) expression in retinoblastoma cell lines that overexpress MdmX, suggesting that they specifically target MdmX and/or Mdm2. Our results document structure-activity relationships for lead-like small molecules targeting MdmX and suggest a strategy for their further optimization in the future by using NMR spectroscopy to monitor small-molecule-induced protein order as manifested through hydrogen bond formation.
Monitoring Ligand-Induced Protein Ordering in Drug Discovery.,Grace CR, Ban D, Min J, Mayasundari A, Min L, Finch KE, Griffiths L, Bharatham N, Bashford D, Kiplin Guy R, Dyer MA, Kriwacki RW J Mol Biol. 2016 Mar 27;428(6):1290-303. doi: 10.1016/j.jmb.2016.01.016. Epub, 2016 Jan 23. PMID:26812210[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
- ↑ Grace CR, Ban D, Min J, Mayasundari A, Min L, Finch KE, Griffiths L, Bharatham N, Bashford D, Kiplin Guy R, Dyer MA, Kriwacki RW. Monitoring Ligand-Induced Protein Ordering in Drug Discovery. J Mol Biol. 2016 Mar 27;428(6):1290-303. doi: 10.1016/j.jmb.2016.01.016. Epub, 2016 Jan 23. PMID:26812210 doi:http://dx.doi.org/10.1016/j.jmb.2016.01.016
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