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==Co-crystal structure of MDM2 with inhibitor (2S,5R,6S)-2-benzyl-5,6-bis(4-chlorophenyl)-4-methylmorpholin-3-one==
==Co-crystal structure of MDM2 with inhibitor (2S,5R,6S)-2-benzyl-5,6-bis(4-chlorophenyl)-4-methylmorpholin-3-one==
<StructureSection load='4jv9' size='340' side='right' caption='[[4jv9]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
<StructureSection load='4jv9' size='340' side='right'caption='[[4jv9]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4jv9]] 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=4JV9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JV9 FirstGlance]. <br>
<table><tr><td colspan='2'>[[4jv9]] 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=4JV9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JV9 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1MO:(2S,5R,6S)-2-BENZYL-5,6-BIS(4-CHLOROPHENYL)-4-METHYLMORPHOLIN-3-ONE'>1MO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1MO:(2S,5R,6S)-2-BENZYL-5,6-BIS(4-CHLOROPHENYL)-4-METHYLMORPHOLIN-3-ONE'>1MO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4jv7|4jv7]], [[4jve|4jve]], [[4jvr|4jvr]], [[4jwr|4jwr]]</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=4jv9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jv9 OCA], [https://pdbe.org/4jv9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jv9 RCSB], [https://www.ebi.ac.uk/pdbsum/4jv9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jv9 ProSAT]</span></td></tr>
<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>
<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=4jv9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jv9 OCA], [http://pdbe.org/4jv9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4jv9 RCSB], [http://www.ebi.ac.uk/pdbsum/4jv9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4jv9 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[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.  
[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.
== Function ==
== Function ==
[[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>
[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>  
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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==See Also==
==See Also==
*[[MDM2|MDM2]]
*[[MDM2 3D structures|MDM2 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Bartberger, M D]]
[[Category: Large Structures]]
[[Category: Beck, H P]]
[[Category: Bartberger MD]]
[[Category: Cannon, J]]
[[Category: Beck HP]]
[[Category: Huang, X]]
[[Category: Cannon J]]
[[Category: Medina, J C]]
[[Category: Gonzalez-Lopez de Turiso F]]
[[Category: Oliner, J D]]
[[Category: Huang X]]
[[Category: Olson, S H]]
[[Category: Medina JC]]
[[Category: Shaffer, P]]
[[Category: Oliner JD]]
[[Category: Sun, D]]
[[Category: Olson SH]]
[[Category: Turiso, F Gonzalez-Lopez de]]
[[Category: Shaffer P]]
[[Category: Yosup, R]]
[[Category: Sun D]]
[[Category: Ligase-ligase inhibitor complex]]
[[Category: Yosup R]]
[[Category: P53]]
[[Category: Protein-protein interaction]]

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