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Acta Crystallogr D Biol Crystallogr. 2013 Aug;69(Pt 8):1358-66. doi: 10.1107/S0907444913004459. Epub 2013 Jul 13.

The structure of an MDM2-Nutlin-3a complex solved by the use of a validated MDM2 surface-entropy reduction mutant.

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1
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, England.

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.

KEYWORDS:

MDM2; Nutlin-3a; mutant validation; p53; surface-entropy reduction

PMID:
23897459
DOI:
10.1107/S0907444913004459
[Indexed for MEDLINE]
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