Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0189379
Title: Structure-activity studies of Mdm2/Mdm4-binding stapled peptides comprising non-natural amino acids
Authors: Chee S.M.Q.
Wongsantichon J.
Siau J.
Thean D.
Ferrer F.
Robinson R.C. 
Lane D.P.
Brown C.J.
Ghadessy F.J.
Keywords: 6 chlorotryptophan
protein MDM2
protein MDMX
protein p53
tryptophan
unclassified drug
amino acid
MDM2 protein, human
MDM4 protein, human
nuclear protein
oncoprotein
peptide
protein binding
protein MDM2
Article
binding affinity
controlled study
enzyme activation
Escherichia coli
limit of quantitation
nonhuman
protein binding
protein expression
protein function
protein modification
protein purification
amino acid sequence
chemistry
human
metabolism
sequence alignment
structure activity relation
X ray crystallography
Amino Acid Sequence
Amino Acids
Crystallography, X-Ray
Humans
Nuclear Proteins
Peptides
Protein Binding
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-mdm2
Sequence Alignment
Structure-Activity Relationship
Issue Date: 2017
Citation: Chee S.M.Q., Wongsantichon J., Siau J., Thean D., Ferrer F., Robinson R.C., Lane D.P., Brown C.J., Ghadessy F.J. (2017). Structure-activity studies of Mdm2/Mdm4-binding stapled peptides comprising non-natural amino acids. PLoS ONE 12 (12) : e0189379. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0189379
Rights: Attribution 4.0 International
Abstract: As primary p53 antagonists, Mdm2 and the closely related Mdm4 are relevant cancer therapeutic targets. We have previously described a series of cell-permeable stapled peptides that bind to Mdm2 with high affinity, resulting in activation of the p53 tumour suppressor. Within this series, highest affinity was obtained by modification of an obligate tryptophan residue to the non-natural L-6-chlorotryptophan. To understand the structural basis for improved affinity we have solved the crystal structure of this stapled peptide (M011) bound to Mdm2 (residues 6-125) at 1.66 å resolution. Surprisingly, near identity to the structure of a related peptide (M06) without the 6-chloro modification is observed. Further analysis of linear and stapled peptides comprising 6-Me-tryptophan provides mechanistic insight into dual Mdm2/Mdm4 antagonism and confirms L98 of Mdm4 as a mutable steric gate. The results also highlight a possible role of the flexible hinge region in determining Mdm2/Mdm4 plasticity. © 2017 Chee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Source Title: PLoS ONE
URI: https://scholarbank.nus.edu.sg/handle/10635/161243
ISSN: 19326203
DOI: 10.1371/journal.pone.0189379
Rights: Attribution 4.0 International
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