5XXK

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

5XXK の概要

• エントリーDOI: 10.2210/pdb5xxk/pdb
• 分子名称: E3 ubiquitin-protein ligase Mdm2, Hydrocarbon stapled peptide THC-SER-PHE-0EH-GLU-TYR-6CW-ALA-LEU-LEU-MK8-NH2 (3 entities in total)
• 機能のキーワード: e3 ubiqutin ligase, oncoprotein, oncoprotein-inhibitor complex, oncoprotein/inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Nucleus, nucleoplasm: Q00987
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 30379.55

構造登録者

Brown, C.J. (登録日: 2017-07-04, 公開日: 2017-12-27, 最終更新日: 2023-11-22)

主引用文献

Chee, S.M.Q.,Wongsantichon, J.,Siau, J.,Thean, D.,Ferrer, F.,Robinson, R.C.,Lane, D.P.,Brown, C.J.,Ghadessy, F.J.
Structure-activity studies of Mdm2/Mdm4-binding stapled peptides comprising non-natural amino acids.
PLoS ONE, 12:e0189379-e0189379, 2017

PubMed 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.

PubMed: 29228061
DOI: 10.1371/journal.pone.0189379

実験手法

X-RAY DIFFRACTION (1.66 Å)