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

Lookup NU author(s): Professor Jane Endicott, Professor Martin Noble

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Abstract

The p53-binding site of MDM2 holds great promise as a target for therapeutic intervention in MDM2-amplified p53 wildtype 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.


Publication metadata

Author(s): Anil B, Riedinger C, Endicott JA, Noble MEM

Publication type: Article

Publication status: Published

Journal: Acta Crystallographica Section D: Biological Crystallography

Year: 2013

Volume: 69

Issue: 8

Pages: 1358-1366

Print publication date: 01/08/2013

ISSN (print): 0907-4449

ISSN (electronic): 1399-0047

Publisher: Wiley-Blackwell

URL: http://dx.doi.org/10.1107/S0907444913004459

DOI: 10.1107/S0907444913004459


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