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Title: Structure of a stapled peptide antagonist bound to nutlin-resistant Mdm2
Authors: Chee S.M.Q.
Wongsantichon J.
Soo Tng Q.
Robinson R. 
Joseph T.L.
Verma C. 
Lane D.P. 
Brown C.J.
Ghadessy F.J.
Keywords: imidazole derivative
MDM2 protein, human
nutlin 3
piperazine derivative
protein binding
protein MDM2
protein p53
recombinant protein
amino acid sequence
antagonists and inhibitors
binding competition
cell line
chemical structure
fluorescence polarization
molecular dynamics
molecular genetics
protein conformation
protein domain
site directed mutagenesis
X ray crystallography
Amino Acid Sequence
Binding, Competitive
Cell Line
Crystallography, X-Ray
Fluorescence Polarization
Models, Molecular
Molecular Dynamics Simulation
Molecular Sequence Data
Mutagenesis, Site-Directed
Protein Binding
Protein Conformation
Protein Interaction Domains and Motifs
Proto-Oncogene Proteins c-mdm2
Recombinant Proteins
Tumor Suppressor Protein p53
Issue Date: 2014
Citation: Chee S.M.Q., Wongsantichon J., Soo Tng Q., Robinson R., Joseph T.L., Verma C., Lane D.P., Brown C.J., Ghadessy F.J. (2014). Structure of a stapled peptide antagonist bound to nutlin-resistant Mdm2. PLoS ONE 9 (8) : e104914. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: As key negative regulator of the p53 tumour suppressor, Mdm2 is an attractive therapeutic target. Small molecules such as Nutlin have been developed to antagonise Mdm2, resulting in p53-dependent death of tumour cells. We have recently described a mutation in Mdm2 (M62A), which precludes binding of Nutlin, but not p53. This Nutlin-resistant variant is not, however, refractory to binding and inhibition by stapled peptide antagonists targeting the same region of Mdm2. A detailed understanding of how stapled peptides are recalcitrant to Mdm2 mutations conferring Nutlin-resistance will aid in the further development of potent Mdm2 antagonists. Here, we report the 2.00 Å crystal structure of a stapled peptide antagonist bound to Nutlin resistant Mdm2. The stapled peptide relies on an extended network of interactions along the hydrophobic binding cleft of Mdm2 for high affinity binding. Additionally, as seen in other stapled peptide structures, the hydrocarbon staple itself contributes to binding through favourable interactions with Mdm2. The structure highlights the intrinsic plasticity present in both Mdm2 and the hydrocarbon staple moiety, and can be used to guide future iterations of both small molecules and stapled peptides for improved antagonists of Mdm2. © 2014 Chee et al.
Source Title: PLoS ONE
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0104914
Rights: Attribution 4.0 International
Appears in Collections:Staff Publications

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