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==The 1.7A crystal structure of humanized Xenopus MDM2 with RO5045337==
==The 1.7A crystal structure of humanized Xenopus MDM2 with RO5045337==
<StructureSection load='4ipf' size='340' side='right' caption='[[4ipf]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
<StructureSection load='4ipf' size='340' side='right'caption='[[4ipf]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4ipf]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Xenopus_laevis Xenopus laevis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4IPF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4IPF FirstGlance]. <br>
<table><tr><td colspan='2'>[[4ipf]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Xenopus_laevis Xenopus laevis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4IPF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IPF FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1F0:[(4S,5R)-2-(4-TERT-BUTYL-2-ETHOXYPHENYL)-4,5-BIS(4-CHLOROPHENYL)-4,5-DIMETHYL-4,5-DIHYDRO-1H-IMIDAZOL-1-YL]{4-[3-(METHYLSULFONYL)PROPYL]PIPERAZIN-1-YL}METHANONE'>1F0</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.7&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1rv1|1rv1]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1F0:[(4S,5R)-2-(4-TERT-BUTYL-2-ETHOXYPHENYL)-4,5-BIS(4-CHLOROPHENYL)-4,5-DIMETHYL-4,5-DIHYDRO-1H-IMIDAZOL-1-YL]{4-[3-(METHYLSULFONYL)PROPYL]PIPERAZIN-1-YL}METHANONE'>1F0</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=8355 Xenopus laevis])</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=4ipf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ipf OCA], [https://pdbe.org/4ipf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ipf RCSB], [https://www.ebi.ac.uk/pdbsum/4ipf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ipf 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=4ipf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ipf OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ipf RCSB], [http://www.ebi.ac.uk/pdbsum/4ipf PDBsum]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/MDM2_XENLA MDM2_XENLA]] E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degration by the proteasome (By similarity).  
[https://www.uniprot.org/uniprot/MDM2_XENLA MDM2_XENLA] E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degration by the proteasome (By similarity).
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
MDM2 negatively regulates p53 stability and many human tumors overproduce MDM2 as a mechanism to restrict p53 function. Thus, inhibitors of p53-MDM2 binding that can reactivate p53 in cancer cells may offer an effective approach for cancer therapy. RG7112 is a potent and selective member of the Nutlin family of MDM2 antagonists currently in Phase I clinical studies. RG7112 binds MDM2 with high affinity (KD ~11 nM), blocking its interactions with p53 in vitro. A crystal structure of the RG7112-MDM2 complex revealed that the small molecule binds in the p53 pocket of MDM2 mimicking the interactions of critical p53 amino acid residues. Treatment of cancer cells expressing wild-type p53 with RG7112 activated the p53 pathway, leading to cell cycle arrest and apoptosis. RG7112 showed potent antitumor activity against a panel of solid tumor cell lines. However, its apoptotic activity varied widely with the best response observed in osteosarcoma cells with MDM2 gene amplification. Interestingly, inhibition of caspase activity did not change the kinetics of p53-induced cell death. Oral administration of RG7112 to human xenograft-bearing mice at non-toxic concentrations caused dosedependent changes in proliferation/apoptosis biomarkers as well as tumor inhibition and regression. Notably, RG7112 was highly synergistic with androgen deprivation in LNCaP xenograft tumors. Our findings offer a preclinical proof-of-concept that RG7112 is effective in treatment of solid tumors expressing wild-type p53.
 
MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models.,Tovar C, Graves B, Packman K, Filipovic Z, Higgins B, Xia M, Tardell C, Garrido R, Lee E, Kolinsky K, To KH, Linn M, Podlaski F, Wovkulich P, Vu B, Vassilev LT Cancer Res. 2013 Feb 11. PMID:23400593<ref>PMID:23400593</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>


==See Also==
==See Also==
*[[MDM2|MDM2]]
*[[MDM2 3D structures|MDM2 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Xenopus laevis]]
[[Category: Xenopus laevis]]
[[Category: Crowther, R]]
[[Category: Crowther R]]
[[Category: Graves, B J]]
[[Category: Graves BJ]]
[[Category: Kammlott, R U]]
[[Category: Kammlott RU]]
[[Category: Lukacs, C]]
[[Category: Lukacs C]]
[[Category: E3 ubiquitin ligase]]
[[Category: Imidazoline]]
[[Category: Ligase-antagonist complex]]
[[Category: Mdm2]]
[[Category: Nucleus]]
[[Category: P53]]
[[Category: Protein-protein interaction]]

Latest revision as of 14:58, 1 March 2024

The 1.7A crystal structure of humanized Xenopus MDM2 with RO5045337The 1.7A crystal structure of humanized Xenopus MDM2 with RO5045337

Structural highlights

4ipf is a 1 chain structure with sequence from Xenopus laevis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.7Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MDM2_XENLA E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degration by the proteasome (By similarity).

See Also

4ipf, resolution 1.70Å

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