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