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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 |
Appears in Collections: | Staff Publications Elements |
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