4HG7

Crystal Structure of an MDM2/Nutlin-3a complex

Summary for 4HG7

• Entry DOI: 10.2210/pdb4hg7/pdb
• Related: 4HFZ
• Descriptor: E3 ubiquitin-protein ligase Mdm2, 4-({(4S,5R)-4,5-bis(4-chlorophenyl)-2-[4-methoxy-2-(propan-2-yloxy)phenyl]-4,5-dihydro-1H-imidazol-1-yl}carbonyl)piperazin-2-one, SULFATE ION, ... (4 entities in total)
• Functional Keywords: mdm2, nutlin-3a, surface entropy reduction, mutant validation, ligase
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus, nucleoplasm: Q00987
• Total number of polymer chains: 1
• Total formula weight: 11759.50

Authors

Noble, M.E.M.,Anil, B.,Riedinger, C.,Endicott, J.A. (deposition date: 2012-10-07, release date: 2013-07-31, Last modification date: 2024-02-28)

Primary citation

Anil, B.,Riedinger, C.,Endicott, J.A.,Noble, M.E.
The structure of an MDM2-Nutlin-3a complex solved by the use of a validated MDM2 surface-entropy reduction mutant.
Acta Crystallogr.,Sect.D, 69:1358-1366, 2013

PubMed Abstract: The p53-binding site of MDM2 holds great promise as a target for therapeutic intervention in MDM2-amplified p53 wild-type forms of cancer. Despite the extensive validation of this strategy, there are relatively few crystallographically determined co-complex structures for small-molecular inhibitors of the MDM2-p53 interaction available in the PDB. Here, a surface-entropy reduction mutant of the N-terminal domain of MDM2 that has been designed to enhance crystallogenesis is presented. This mutant has been validated by comparative ligand-binding studies using differential scanning fluorimetry and fluorescence polarization anisotropy and by cocrystallization with a peptide derived from p53. Using this mutant, the cocrystal structure of MDM2 with the benchmark inhibitor Nutlin-3a has been determined, revealing subtle differences from the previously described co-complex of MDM2 with Nutlin-2.

PubMed: 23897459
DOI: 10.1107/S0907444913004459

Experimental method

X-RAY DIFFRACTION (1.6 Å)