9FQL

Crystal structure of hDM2 in complex with a peptidic ligand containing a di-urea insert.

9FQL の概要

• エントリーDOI: 10.2210/pdb9fql/pdb
• 分子名称: E3 ubiquitin-protein ligase Mdm2, p25Lp26A, PHOSPHATE ION, ... (4 entities in total)
• 機能のキーワード: protein foldamer complex, protein foldamer interactions, protein protein interaction inhibitor, urea based chimera foldamer, antitumor protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 69526.24

構造登録者

Buratto, J.,Mauran, L.,Goudreau, S.,Guichard, G. (登録日: 2024-06-17, 公開日: 2025-07-02, 最終更新日: 2026-01-28)

主引用文献

Neuville, M.,Bourgeais, M.,Buratto, J.,Saragaglia, C.,Li, B.,Galeano-Otero, I.,Mauran, L.,Varajao, L.,Goudreau, S.R.,Kauffmann, B.,Thinon, E.,Pasco, M.,Khatib, A.M.,Guichard, G.
Optimal Stapling of a Helical Peptide-Foldamer Hybrid Using a C-Terminal 4-Mercaptoproline Enhances Protein Surface Recognition and Cellular Activity.
Chemistry, 31:e202403330-e202403330, 2025

PubMed Abstract: Structural analysis of a co-crystal of a helically-folded peptide-foldamer hybrid in complex with hDM2 E3 ubiquitin ligase, revealed a unique orientation for the C-terminal proline with the pyrrolidine ring pointing backwards in the sequence, and suggested new opportunities for macrocyclization. In particular, we found that the C-terminal prolyl residue could be replaced by its (2S,4S)-4-mercaptoprolyl analogue for optimal bisthioether crosslinking with a cysteine residue installed at position 4 in the sequence. The resulting i,i+7 stapled peptide-foldamer is a high-affinity binder to hDM2, is cell permeable and restores the p53 signalling pathway in p53wt cancer cells. The co-crystal structure of hDM2 and the stapled peptide-foldamer hybrid was determined at 1.84 Å, fully validating the original design and further highlighting the potential of cis-4-mercaptoproline in the context of peptide and foldamer stapling.

PubMed: 40014761
DOI: 10.1002/chem.202403330

実験手法

X-RAY DIFFRACTION (2 Å)