7CDC

Crystal structure of LSD1-CoREST in complex with PRSFLVRRP peptide

7CDC の概要

• エントリーDOI: 10.2210/pdb7cdc/pdb
• 分子名称: Lysine-specific histone demethylase 1A, REST corepressor 1, PRO-ARG-SER-PHE-LEU-VAL-ARG-ARG-PRO, ... (6 entities in total)
• 機能のキーワード: demethylase, amine oxidase, chromatin, histone, fad, corepressor, oxidoreductase-transcription-inhibitor complex, oxidoreductase, oxidoreductase-transcription complex, oxidoreductase/transcription
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 92284.07

構造登録者

Kikuchi, M.,Kitagawa, H.,Sato, S.,Umezawa, N.,Higuchi, T.,Umehara, T. (登録日: 2020-06-19, 公開日: 2021-06-23, 最終更新日: 2023-11-29)

主引用文献

Kitagawa, H.,Kikuchi, M.,Sato, S.,Watanabe, H.,Umezawa, N.,Kato, M.,Hisamatsu, Y.,Umehara, T.,Higuchi, T.
Structure-Based Identification of Potent Lysine-Specific Demethylase 1 Inhibitor Peptides and Temporary Cyclization to Enhance Proteolytic Stability and Cell Growth-Inhibitory Activity.
J.Med.Chem., 64:3707-3719, 2021

PubMed Abstract: Peptides are attractive drug candidates, but their utility is greatly limited by their inherent susceptibility to proteolytic degradation and their inability to pass through the cell membrane. Here, we employ a strategy of temporary cyclization to develop a cell-active lysine-specific demethylase 1 (LSD1/KDM1A) inhibitor peptide. We first identified a highly potent LSD1-inhibitory linear peptide, with the assistance of X-ray crystal structure data of inhibitor peptide-bound LSD1·CoREST. The peptide was converted to a redox-activatable cyclic peptide incorporating cell-penetrating peptide (CPP), expecting selective activation under intracellular reducing conditions. The cyclic peptide moiety exhibited enhanced stability to protease and was converted to the linear, unmodified LSD1 inhibitor peptide under reducing conditions. The cyclic peptide with CPP inhibited the proliferation of human acute myeloid leukemia cells (HL-60) in the low micromolar concentration range.

PubMed: 33754721
DOI: 10.1021/acs.jmedchem.0c01371

実験手法

X-RAY DIFFRACTION (2.64 Å)