3LBK

Structure of human MDM2 protein in complex with a small molecule inhibitor

Summary for 3LBK

• Entry DOI: 10.2210/pdb3lbk/pdb
• Related: 1YCR 3LBJ 3LBL
• Descriptor: E3 ubiquitin-protein ligase Mdm2, 6-chloro-3-[1-(4-chlorobenzyl)-4-phenyl-1H-imidazol-5-yl]-1H-indole-2-carboxylic acid, SULFATE ION, ... (4 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: 1
• Total formula weight: 11717.46

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 (2.3 Å)