Please use this identifier to cite or link to this item:
https://doi.org/10.1371/journal.pone.0189379
DC Field | Value | |
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dc.title | Structure-activity studies of Mdm2/Mdm4-binding stapled peptides comprising non-natural amino acids | |
dc.contributor.author | Chee S.M.Q. | |
dc.contributor.author | Wongsantichon J. | |
dc.contributor.author | Siau J. | |
dc.contributor.author | Thean D. | |
dc.contributor.author | Ferrer F. | |
dc.contributor.author | Robinson R.C. | |
dc.contributor.author | Lane D.P. | |
dc.contributor.author | Brown C.J. | |
dc.contributor.author | Ghadessy F.J. | |
dc.date.accessioned | 2019-11-01T08:18:29Z | |
dc.date.available | 2019-11-01T08:18:29Z | |
dc.date.issued | 2017 | |
dc.identifier.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 | |
dc.identifier.issn | 19326203 | |
dc.identifier.uri | https://scholarbank.nus.edu.sg/handle/10635/161243 | |
dc.description.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. | |
dc.rights | Attribution 4.0 International | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.source | Unpaywall 20191101 | |
dc.subject | 6 chlorotryptophan | |
dc.subject | protein MDM2 | |
dc.subject | protein MDMX | |
dc.subject | protein p53 | |
dc.subject | tryptophan | |
dc.subject | unclassified drug | |
dc.subject | amino acid | |
dc.subject | MDM2 protein, human | |
dc.subject | MDM4 protein, human | |
dc.subject | nuclear protein | |
dc.subject | oncoprotein | |
dc.subject | peptide | |
dc.subject | protein binding | |
dc.subject | protein MDM2 | |
dc.subject | Article | |
dc.subject | binding affinity | |
dc.subject | controlled study | |
dc.subject | enzyme activation | |
dc.subject | Escherichia coli | |
dc.subject | limit of quantitation | |
dc.subject | nonhuman | |
dc.subject | protein binding | |
dc.subject | protein expression | |
dc.subject | protein function | |
dc.subject | protein modification | |
dc.subject | protein purification | |
dc.subject | amino acid sequence | |
dc.subject | chemistry | |
dc.subject | human | |
dc.subject | metabolism | |
dc.subject | sequence alignment | |
dc.subject | structure activity relation | |
dc.subject | X ray crystallography | |
dc.subject | Amino Acid Sequence | |
dc.subject | Amino Acids | |
dc.subject | Crystallography, X-Ray | |
dc.subject | Humans | |
dc.subject | Nuclear Proteins | |
dc.subject | Peptides | |
dc.subject | Protein Binding | |
dc.subject | Proto-Oncogene Proteins | |
dc.subject | Proto-Oncogene Proteins c-mdm2 | |
dc.subject | Sequence Alignment | |
dc.subject | Structure-Activity Relationship | |
dc.type | Article | |
dc.contributor.department | BIOCHEMISTRY | |
dc.contributor.department | CHEMICAL & BIOMOLECULAR ENGINEERING | |
dc.description.doi | 10.1371/journal.pone.0189379 | |
dc.description.sourcetitle | PLoS ONE | |
dc.description.volume | 12 | |
dc.description.issue | 12 | |
dc.description.page | e0189379 | |
Appears in Collections: | Staff Publications Elements |
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