3VBG

Structure of hDM2 with Dimer Inducing Indolyl Hydantoin RO-2443

Summary for 3VBG

• Entry DOI: 10.2210/pdb3vbg/pdb
• Related: 1RV1 3U15
• Descriptor: E3 ubiquitin-protein ligase Mdm2, (5Z)-5-[(6-chloro-7-methyl-1H-indol-3-yl)methylidene]-3-(3,4-difluorobenzyl)imidazolidine-2,4-dione (3 entities in total)
• Functional Keywords: ligase, mdm2, mdmx, p53, ligase-ligase activator complex, ligase/ligase activator
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 41850.56

Authors

Lukacs, C.M.,Janson, C.A.,Graves, B.J. (deposition date: 2012-01-02, release date: 2012-06-27, Last modification date: 2023-09-13)

Primary citation

Graves, B.,Thompson, T.,Xia, M.,Janson, C.,Lukacs, C.,Deo, D.,Di Lello, P.,Fry, D.,Garvie, C.,Huang, K.S.,Gao, L.,Tovar, C.,Lovey, A.,Wanner, J.,Vassilev, L.T.
Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization.
Proc.Natl.Acad.Sci.USA, 109:11788-11793, 2012

PubMed Abstract: Activation of p53 tumor suppressor by antagonizing its negative regulator murine double minute (MDM)2 has been considered an attractive strategy for cancer therapy and several classes of p53-MDM2 binding inhibitors have been developed. However, these compounds do not inhibit the p53-MDMX interaction, and their effectiveness can be compromised in tumors overexpressing MDMX. Here, we identify small molecules that potently block p53 binding with both MDM2 and MDMX by inhibitor-driven homo- and/or heterodimerization of MDM2 and MDMX proteins. Structural studies revealed that the inhibitors bind into and occlude the p53 pockets of MDM2 and MDMX by inducing the formation of dimeric protein complexes kept together by a dimeric small-molecule core. This mode of action effectively stabilized p53 and activated p53 signaling in cancer cells, leading to cell cycle arrest and apoptosis. Dual MDM2/MDMX antagonists restored p53 apoptotic activity in the presence of high levels of MDMX and may offer a more effective therapeutic modality for MDMX-overexpressing cancers.

PubMed: 22745160
DOI: 10.1073/pnas.1203789109

Experimental method

X-RAY DIFFRACTION (2.8 Å)