6F0F

Crystal structure ASF1-ip2_s

6F0F の概要

• エントリーDOI: 10.2210/pdb6f0f/pdb
• 関連するPDBエントリー: 6F0E 6F0H
• 分子名称: Histone chaperone ASF1A, ip2_s (3 entities in total)
• 機能のキーワード: protein-peptide complexe, chaperone
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 20891.40

構造登録者

Gaubert, A.,Guichard, B.,Murciano, B.,Le Du, M.H.,Ochsenbein, F.,Guerois, R.,Andreani, J. (登録日: 2017-11-20, 公開日: 2019-06-12, 最終更新日: 2024-01-17)

主引用文献

Bakail, M.,Gaubert, A.,Andreani, J.,Moal, G.,Pinna, G.,Boyarchuk, E.,Gaillard, M.C.,Courbeyrette, R.,Mann, C.,Thuret, J.Y.,Guichard, B.,Murciano, B.,Richet, N.,Poitou, A.,Frederic, C.,Le Du, M.H.,Agez, M.,Roelants, C.,Gurard-Levin, Z.A.,Almouzni, G.,Cherradi, N.,Guerois, R.,Ochsenbein, F.
Design on a Rational Basis of High-Affinity Peptides Inhibiting the Histone Chaperone ASF1.
Cell Chem Biol, 26:1573-1585.e10, 2019

PubMed Abstract: Anti-silencing function 1 (ASF1) is a conserved H3-H4 histone chaperone involved in histone dynamics during replication, transcription, and DNA repair. Overexpressed in proliferating tissues including many tumors, ASF1 has emerged as a promising therapeutic target. Here, we combine structural, computational, and biochemical approaches to design peptides that inhibit the ASF1-histone interaction. Starting from the structure of the human ASF1-histone complex, we developed a rational design strategy combining epitope tethering and optimization of interface contacts to identify a potent peptide inhibitor with a dissociation constant of 3 nM. When introduced into cultured cells, the inhibitors impair cell proliferation, perturb cell-cycle progression, and reduce cell migration and invasion in a manner commensurate with their affinity for ASF1. Finally, we find that direct injection of the most potent ASF1 peptide inhibitor in mouse allografts reduces tumor growth. Our results open new avenues to use ASF1 inhibitors as promising leads for cancer therapy.

PubMed: 31543461
DOI: 10.1016/j.chembiol.2019.09.002

実験手法

X-RAY DIFFRACTION (2 Å)