8CAP

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

Summary for 8CAP

• Entry DOI: 10.2210/pdb8cap/pdb
• Descriptor: 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)
• Functional Keywords: ros, inhibitor, redox biology, oxidoreductase
• Biological source: Cylindrospermum stagnale
• Total number of polymer chains: 4
• Total formula weight: 133980.03

Authors

Reis, J.,Mattevi, A. (deposition date: 2023-01-24, release date: 2023-09-27, Last modification date: 2024-04-10)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3 Å)