9GFK

human MDM2 complex with stapled foldamer

This is a non-PDB format compatible entry.

Summary for 9GFK

• Entry DOI: 10.2210/pdb9gfk/pdb
• Descriptor: E3 ubiquitin-protein ligase Mdm2, Stapled foldamer, SULFATE ION, ... (4 entities in total)
• Functional Keywords: hdm2, staple peptide, helical peptide-foldamer, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 51216.31

Authors

Neuville, M.,Bourgeais, M.,Buratto, J.,Saragaglia, C.,Bo, L.,Mauran, L.,Varajao, L.,Goudreau, S.R.,Kauffmann, B.,Thinon, E.,Pasco, M.,Khatib, A.M. (deposition date: 2024-08-09, release date: 2025-03-26, Last modification date: 2025-04-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.841 Å)