3LBL

Structure of human MDM2 protein in complex with Mi-63-analog

Summary for 3LBL

• Entry DOI: 10.2210/pdb3lbl/pdb
• Related: 1YCR 3LBJ 3LBK
• Descriptor: E3 ubiquitin-protein ligase Mdm2, (2'R,3R,4'R,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-N-(2-morpholin-4-ylethyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxamide (3 entities in total)
• Functional Keywords: mdmx, mdm2, p53, inhibitor, alternative splicing, cytoplasm, ligase, nucleus, phosphoprotein, proto-oncogene, ubl conjugation, ubl conjugation pathway, zinc-finger
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 35161.91

Authors

Popowicz, G.M.,Czarna, A.,Wolf, S.,Holak, T.A. (deposition date: 2010-01-08, release date: 2010-03-16, Last modification date: 2023-11-01)

Primary citation

Popowicz, G.M.,Czarna, A.,Wolf, S.,Wang, K.,Wang, W.,Domling, A.,Holak, T.A.
Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery
Cell Cycle, 9:1104-1111, 2010

PubMed Abstract: Intensive anticancer drug discovery efforts have been made to develop small molecule inhibitors of the p53-MDM2 and p53-MDMX interactions. We present here the structures of the most potent inhibitors bound to MDM2 and MDMX that are based on the new imidazo-indole scaffold. In addition, the structure of the recently reported spiro-oxindole inhibitor bound to MDM2 is described. The structures indicate how the substituents of a small molecule that bind to the three subpockets of the MDM2/X-p53 interaction should be optimized for effective binding to MDM2 and/or MDMX. While the spiro-oxindole inhibitor triggers significant ligand-induced changes in MDM2, the imidazo-indoles share similar binding modes for MDMX and MDM2, but cause only minimal induced-fit changes in the structures of both proteins. Our study includes the first structure of the complex between MDMX and a small molecule and should aid in developing efficient scaffolds for binding to MDMX and/or MDM2.

PubMed: 20237429
DOI: 10.4161/cc.9.6.10956

Experimental method

X-RAY DIFFRACTION (1.6 Å)