9SS3

Crystal structure hASF1A 156-cr7

This is a non-PDB format compatible entry.

Summary for 9SS3

• Entry DOI: 10.2210/pdb9ss3/pdb
• Descriptor: Histone chaperone ASF1A, cr7, GLYCEROL, ... (4 entities in total)
• Functional Keywords: protein inhibitor, asf1, histone chaperone, protein-protein interaction, cancer, chaperone
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 20206.85

Authors

Ochsenbein, F.O.,Vitard, A.V.,Perrin, M.P. (deposition date: 2025-09-25, release date: 2026-09-02)

Primary citation

Li, B.,Perrin, M.E.,Maillard, E.,Vitard, A.,Moal, G.,Mbianda, J.,Andre, C.,Teixeira Nunes, M.,Vandamme, M.,Pinna, G.,Douat, C.,Thinon, E.,Guerois, R.,Legrand, P.,Guichard, G.,Ochsenbein, F.
Downsizing the Histone H3-H4 Quaternary Structure Into Foldamer Mimetics Yields High-Affinity and Cell-Permeable Ligands of ASF1.
Angew.Chem.Int.Ed.Engl., :e4112426-e4112426, 2026

PubMed Abstract: Mimicking complex protein-protein interfaces with small, well-defined molecular scaffolds remains a major challenge in chemical biology. Here, we report a foldamer-based downsizing strategy that compresses the quaternary architecture of the histone H3-H4 dimer into compact peptide-oligourea hybrids acting as high-affinity ligands of the histone chaperone Anti-Silencing Function 1 (ASF1). Guided by multiple high-resolution co-crystal structures, we designed a series of foldamer mimetics that accurately reproduce both the H3 α-helix and the H4 β-strand epitopes. Systematic optimization of linker geometry, β-strand mimicry, formal charge, and selective backbone N-methylation yielded highly stable ligands with nanomolar affinities, enhanced proteolytic resistance, and robust cytosolic penetration. Notably, the optimized constructs and their N-methylated analogues recapitulate the binding mode of the native H3-H4 dimer on ASF1 with high fidelity and engage endogenous ASF1 in cell extracts, demonstrating effective intracellular target recognition. Together, these results show that peptide-oligourea foldamers can reproduce the structural features of a protein quaternary structure surface, combining high affinity, high stability and cell permeability.

PubMed: 42585141
DOI: 10.1002/anie.4112426

Experimental method

X-RAY DIFFRACTION (1.999 Å)