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| | ==Structure of human MDMX protein in complex with a small molecule inhibitor== | | ==Structure of human MDMX protein in complex with a small molecule inhibitor== |
| - | <StructureSection load='3lbj' size='340' side='right' caption='[[3lbj]], [[Resolution|resolution]] 1.50Å' scene=''> | + | <StructureSection load='3lbj' size='340' side='right'caption='[[3lbj]], [[Resolution|resolution]] 1.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3lbj]] is a 1 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=3LBJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3LBJ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3lbj]] is a 1 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=3LBJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3LBJ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=WW8:N-[(3S)-1-({6-CHLORO-3-[1-(4-CHLOROBENZYL)-4-PHENYL-1H-IMIDAZOL-5-YL]-1H-INDOL-2-YL}CARBONYL)PYRROLIDIN-3-YL]-N,N,N-TRIMETHYLPROPANE-1,3-DIAMINE'>WW8</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]] 1.5Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3dab|3dab]], [[3lbk|3lbk]], [[3lbl|3lbl]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=WW8:N-[(3S)-1-({6-CHLORO-3-[1-(4-CHLOROBENZYL)-4-PHENYL-1H-IMIDAZOL-5-YL]-1H-INDOL-2-YL}CARBONYL)PYRROLIDIN-3-YL]-N,N,N-TRIMETHYLPROPANE-1,3-DIAMINE'>WW8</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MDM4, MDMX ([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'>[https://proteopedia.org/fgij/fg.htm?mol=3lbj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3lbj OCA], [https://pdbe.org/3lbj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3lbj RCSB], [https://www.ebi.ac.uk/pdbsum/3lbj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3lbj ProSAT]</span></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=3lbj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3lbj OCA], [http://pdbe.org/3lbj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3lbj RCSB], [http://www.ebi.ac.uk/pdbsum/3lbj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3lbj 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> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Czarna, A]] | + | [[Category: Large Structures]] |
| - | [[Category: Holak, T A]] | + | [[Category: Czarna A]] |
| - | [[Category: Popowicz, G M]] | + | [[Category: Holak TA]] |
| - | [[Category: Wolf, S]] | + | [[Category: Popowicz GM]] |
| - | [[Category: Alternative splicing]] | + | [[Category: Wolf S]] |
| - | [[Category: Cell cycle]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Mdm2]]
| + | |
| - | [[Category: Mdmx]]
| + | |
| - | [[Category: Nucleus]]
| + | |
| - | [[Category: P53]]
| + | |
| - | [[Category: Polymorphism]]
| + | |
| - | [[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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Intensive anticancer drug discovery efforts have been made to develop small molecule inhibitors of the p53-MDM2 and p53-MDMX interactions. We present here the structures of the most potent inhibitors bound to MDM2 and MDMX that are based on the new imidazo-indole scaffold. In addition, the structure of the recently reported spiro-oxindole inhibitor bound to MDM2 is described. The structures indicate how the substituents of a small molecule that bind to the three subpockets of the MDM2/X-p53 interaction should be optimized for effective binding to MDM2 and/or MDMX. While the spiro-oxindole inhibitor triggers significant ligand-induced changes in MDM2, the imidazo-indoles share similar binding modes for MDMX and MDM2, but cause only minimal induced-fit changes in the structures of both proteins. Our study includes the first structure of the complex between MDMX and a small molecule and should aid in developing efficient scaffolds for binding to MDMX and/or MDM2.
Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery.,Popowicz GM, Czarna A, Wolf S, Wang K, Wang W, Domling A, Holak TA Cell Cycle. 2010 Mar 15;9(6):1104-11. doi: 10.4161/cc.9.6.10956. Epub 2010 Mar, 15. PMID:20237429[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
- ↑ Popowicz GM, Czarna A, Wolf S, Wang K, Wang W, Domling A, Holak TA. Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery. Cell Cycle. 2010 Mar 15;9(6):1104-11. doi: 10.4161/cc.9.6.10956. Epub 2010 Mar, 15. PMID:20237429 doi:http://dx.doi.org/10.4161/cc.9.6.10956
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