Structure-activity studies of Mdm2/Mdm4-binding stapled peptides comprising non-natural amino acids

Sharon Min Qi Chee, Jantana Wongsantichon, Jiawei Siau, Dawn Thean, Fernando Ferrer, Robert C. Robinson, David P. Lane, Christopher J. Brown, Farid J. Ghadessy

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Article numbere0189379
JournalPloS one
Volume12
Issue number12
DOIs
Publication statusPublished - Dec 2017
Externally publishedYes

Fingerprint

peptides
Amino Acids
Peptides
amino acids
Tryptophan
tryptophan
neoplasms
Hinges
crystal structure
Plasticity
Tumors
antagonists
Neoplasms
Crystal structure
Chemical activation
therapeutics
cells
Therapeutics
6-chlorotryptophan

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Chee, S. M. Q., Wongsantichon, J., Siau, J., Thean, D., Ferrer, F., Robinson, R. C., ... Ghadessy, F. J. (2017). Structure-activity studies of Mdm2/Mdm4-binding stapled peptides comprising non-natural amino acids. PloS one, 12(12), [e0189379]. https://doi.org/10.1371/journal.pone.0189379

Structure-activity studies of Mdm2/Mdm4-binding stapled peptides comprising non-natural amino acids. / Chee, Sharon Min Qi; Wongsantichon, Jantana; Siau, Jiawei; Thean, Dawn; Ferrer, Fernando; Robinson, Robert C.; Lane, David P.; Brown, Christopher J.; Ghadessy, Farid J.

In: PloS one, Vol. 12, No. 12, e0189379, 12.2017.

Research output: Contribution to journalArticle

Chee, SMQ, Wongsantichon, J, Siau, J, Thean, D, Ferrer, F, Robinson, RC, Lane, DP, Brown, CJ & Ghadessy, FJ 2017, 'Structure-activity studies of Mdm2/Mdm4-binding stapled peptides comprising non-natural amino acids', PloS one, vol. 12, no. 12, e0189379. https://doi.org/10.1371/journal.pone.0189379
Chee, Sharon Min Qi ; Wongsantichon, Jantana ; Siau, Jiawei ; Thean, Dawn ; Ferrer, Fernando ; Robinson, Robert C. ; Lane, David P. ; Brown, Christopher J. ; Ghadessy, Farid J. / Structure-activity studies of Mdm2/Mdm4-binding stapled peptides comprising non-natural amino acids. In: PloS one. 2017 ; Vol. 12, No. 12.
@article{7ddd86ed40aa48f28a4ccb9abd825c6d,
title = "Structure-activity studies of Mdm2/Mdm4-binding stapled peptides comprising non-natural amino acids",
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 {\aa} 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.",
author = "Chee, {Sharon Min Qi} and Jantana Wongsantichon and Jiawei Siau and Dawn Thean and Fernando Ferrer and Robinson, {Robert C.} and Lane, {David P.} and Brown, {Christopher J.} and Ghadessy, {Farid J.}",
year = "2017",
month = "12",
doi = "10.1371/journal.pone.0189379",
language = "English",
volume = "12",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "12",

}

TY - JOUR

T1 - Structure-activity studies of Mdm2/Mdm4-binding stapled peptides comprising non-natural amino acids

AU - Chee, Sharon Min Qi

AU - Wongsantichon, Jantana

AU - Siau, Jiawei

AU - Thean, Dawn

AU - Ferrer, Fernando

AU - Robinson, Robert C.

AU - Lane, David P.

AU - Brown, Christopher J.

AU - Ghadessy, Farid J.

PY - 2017/12

Y1 - 2017/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85038422453&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85038422453&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0189379

DO - 10.1371/journal.pone.0189379

M3 - Article

C2 - 29228061

AN - SCOPUS:85038422453

VL - 12

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 12

M1 - e0189379

ER -