4ZFI

Structure of Mdm2 with low molecular weight inhibitor

Summary for 4ZFI

• Entry DOI: 10.2210/pdb4zfi/pdb
• Descriptor: E3 ubiquitin-protein ligase Mdm2, (5S)-3,5-bis(4-chlorobenzyl)-4-(6-chloro-1H-indol-3-yl)-5-hydroxy-1-methyl-1,5-dihydro-2H-pyrrol-2-one (3 entities in total)
• Functional Keywords: p53-binding protein mdm2, oncoprotein mdm2, double minute 2 protein, hdm2, small molecule inhibitor, ligase
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus, nucleoplasm: Q00987
• Total number of polymer chains: 4
• Total formula weight: 47644.81

Authors

Zak, K.M.,Twarda-Clapa, A.,Wrona, E.M.,Grudnik, P.,Dubin, G.,Holak, T.A. (deposition date: 2015-04-21, release date: 2016-10-19, Last modification date: 2024-01-10)

Primary citation

Surmiak, E.,Twarda-Clapa, A.,Zak, K.M.,Musielak, B.,Tomala, M.D.,Kubica, K.,Grudnik, P.,Madej, M.,Jablonski, M.,Potempa, J.,Kalinowska-Tluscik, J.,Domling, A.,Dubin, G.,Holak, T.A.
A Unique Mdm2-Binding Mode of the 3-Pyrrolin-2-one- and 2-Furanone-Based Antagonists of the p53-Mdm2 Interaction.
ACS Chem. Biol., 11:3310-3318, 2016

PubMed Abstract: The p53 pathway is inactivated in almost all types of cancer by mutations in the p53 encoding gene or overexpression of the p53 negative regulators, Mdm2 and/or Mdmx. Restoration of the p53 function by inhibition of the p53-Mdm2/Mdmx interaction opens up a prospect for a nongenotoxic anticancer therapy. Here, we present the syntheses, activities, and crystal structures of two novel classes of Mdm2-p53 inhibitors that are based on the 3-pyrrolin-2-one and 2-furanone scaffolds. The structures of the complexes formed by these inhibitors and Mdm2 reveal the dimeric protein molecular organization that has not been observed in the small-molecule/Mdm2 complexes described until now. In particular, the 6-chloroindole group does not occupy the usual Trp-23 pocket of Mdm2 but instead is engaged in dimerization. This entirely unique binding mode of the compounds opens new possibilities for optimization of the Mdm2-p53 interaction inhibitors.

PubMed: 27709883
DOI: 10.1021/acschembio.6b00596

Experimental method

X-RAY DIFFRACTION (2 Å)