3VBG

Structure of hDM2 with Dimer Inducing Indolyl Hydantoin RO-2443

3VBG の概要

• エントリーDOI: 10.2210/pdb3vbg/pdb
• 関連するPDBエントリー: 1RV1 3U15
• 分子名称: 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)
• 機能のキーワード: ligase, mdm2, mdmx, p53, ligase-ligase activator complex, ligase/ligase activator
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 41850.56

構造登録者

Lukacs, C.M.,Janson, C.A.,Graves, B.J. (登録日: 2012-01-02, 公開日: 2012-06-27, 最終更新日: 2023-09-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.8 Å)