8CAP

Crystal structure of dehydrogenase domain of Cylindrospermum stagnale NADPH-Oxidase 5 (NOX5) in complex with CB28

8CAP の概要

• エントリーDOI: 10.2210/pdb8cap/pdb
• 分子名称: Putative ferric reductase, FLAVIN-ADENINE DINUCLEOTIDE, [4-[[(4~{E})-4-(furan-2-ylmethylidene)-2,3-dihydro-1~{H}-acridin-9-yl]carbonyl]piperazin-1-yl]-pyridin-2-yl-methanone (3 entities in total)
• 機能のキーワード: ros, inhibitor, redox biology, oxidoreductase
• 由来する生物種: Cylindrospermum stagnale
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 133980.03

構造登録者

Reis, J.,Mattevi, A. (登録日: 2023-01-24, 公開日: 2023-09-27, 最終更新日: 2025-10-01)

主引用文献

Reis, J.,Gorgulla, C.,Massari, M.,Marchese, S.,Valente, S.,Noce, B.,Basile, L.,Torner, R.,Cox 3rd, H.,Viennet, T.,Yang, M.H.,Ronan, M.M.,Rees, M.G.,Roth, J.A.,Capasso, L.,Nebbioso, A.,Altucci, L.,Mai, A.,Arthanari, H.,Mattevi, A.
Targeting ROS production through inhibition of NADPH oxidases.
Nat.Chem.Biol., 19:1540-1550, 2023

PubMed Abstract: NADPH oxidases (NOXs) are transmembrane enzymes that are devoted to the production of reactive oxygen species (ROS). In cancers, dysregulation of NOX enzymes affects ROS production, leading to redox unbalance and tumor progression. Consequently, NOXs are a drug target for cancer therapeutics, although current therapies have off-target effects: there is a need for isoenzyme-selective inhibitors. Here, we describe fully validated human NOX inhibitors, obtained from an in silico screen, targeting the active site of Cylindrospermum stagnale NOX5 (csNOX5). The hits are validated by in vitro and in cellulo enzymatic and binding assays, and their binding modes to the dehydrogenase domain of csNOX5 studied via high-resolution crystal structures. A high-throughput screen in a panel of cancer cells shows activity in selected cancer cell lines and synergistic effects with KRAS modulators. Our work lays the foundation for the development of inhibitor-based methods for controlling the tightly regulated and highly localized ROS sources.

PubMed: 37884805
DOI: 10.1038/s41589-023-01457-5

実験手法

X-RAY DIFFRACTION (3 Å)