期刊
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
卷 69, 期 -, 页码 1358-1366出版社
INT UNION CRYSTALLOGRAPHY
DOI: 10.1107/S0907444913004459
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资金
- MRC [G0700053] Funding Source: UKRI
- Medical Research Council [G0700053] Funding Source: Medline
- Medical Research Council [G0700053] Funding Source: researchfish
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.
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