4MDN

Structure of a novel submicromolar MDM2 inhibitor

Summary for 4MDN

• Entry DOI: 10.2210/pdb4mdn/pdb
• Related: 4MDQ
• Descriptor: E3 ubiquitin-protein ligase Mdm2, 3-{(1S)-2-(tert-butylamino)-1-[{4-[(4-chlorobenzyl)oxy]benzyl}(formyl)amino]-2-oxoethyl}-6-chloro-1H-indole-2-carboxylic acid, SULFATE ION, ... (4 entities in total)
• Functional Keywords: mdm2, p53, cancer, small molecule, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus, nucleoplasm: Q00987
• Total number of polymer chains: 1
• Total formula weight: 11803.62

Authors

Bista, M.,Popowicz, G.,Holak, T.A. (deposition date: 2013-08-23, release date: 2013-11-13, Last modification date: 2024-02-28)

Primary citation

Bista, M.,Wolf, S.,Khoury, K.,Kowalska, K.,Huang, Y.,Wrona, E.,Arciniega, M.,Popowicz, G.M.,Holak, T.A.,Domling, A.
Transient Protein States in Designing Inhibitors of the MDM2-p53 Interaction.
Structure, 21:2143-2151, 2013

PubMed Abstract: Reactivation of p53 by release of the functional protein from its inhibition by MDM2 provides an efficient, nongenotoxic approach to a wide variety of cancers. We present the cocrystal structures of two complexes of MDM2 with inhibitors based on 6-chloroindole scaffolds. Both molecules bound to a distinct conformational state of MDM2 with nM-μM affinities. In contrast to other structurally characterized antagonists, which mimic three amino acids of p53 (Phe19, Trp23, and Leu26), the compounds induced an additional hydrophobic pocket on the MDM2 surface and unveiled a four-point binding mode. The enlarged interaction interface of the inhibitors resulted in extension of small molecules binding toward the "lid" segment of MDM2 (residues 19-23)--a nascent element that interferes with p53 binding. As supported by protein engineering and molecular dynamics studies, employing these unstable elements of MDM2 provides an efficient and yet unexplored alternative in development of MDM2-p53 association inhibitors.

PubMed: 24207125
DOI: 10.1016/j.str.2013.09.006

Experimental method

X-RAY DIFFRACTION (1.905 Å)