Back to Search
Start Over
Crystal structures and atomic model of NADPH oxidase
- Source :
- Proceedings of the National Academy of Science of the United States of America, 114(26), 6764-6769. NATL ACAD SCIENCES
- Publication Year :
- 2017
-
Abstract
- NADPH oxidases (NOXs) are the only enzymes exclusively dedicated to reactive oxygen species (ROS) generation. Dysregulation of these polytopic membrane proteins impacts the redox signaling cascades that control cell proliferation and death. We describe the atomic crystal structures of the catalytic flavin adenine dinucleotide (FAD)and heme-binding domains of Cylindrospermum stagnale NOX5. The two domains form the core subunit that is common to all seven members of the NOX family. The domain structures were then docked in silico to provide a generic model for the NOX family. A linear arrangement of cofactors (NADPH, FAD, and two membrane-embedded heme moieties) injects electrons from the intracellular side across the membrane to a specific oxygen-binding cavity on the extracytoplasmic side. The overall spatial organization of critical interactions is revealed between the intracellular loops on the transmembrane domain and the NADPH-oxidizing dehydrogenase domain. In particular, the C terminus functions as a toggle switch, which affects access of the NADPH substrate to the enzyme. The essence of this mechanistic model is that the regulatory cues conformationally gate NADPH-binding, implicitly providing a handle for activating/deactivating the very first step in the redox chain. Such insight provides a framework to the discovery of much needed drugs that selectively target the distinct members of the NOX family and interfere with ROS signaling.
- Subjects :
- 0301 basic medicine
Protein domain
Dehydrogenase
TRANSMEMBRANE
Crystallography, X-Ray
Cyanobacteria
Cofactor
Protein Structure, Secondary
THERAPEUTIC TARGETS
03 medical and health sciences
chemistry.chemical_compound
NOX5
CYTOCHROME B(558)
Bacterial Proteins
Protein Domains
Oxidoreductase
BINDING
oxidative stress
membrane protein
ELECTRON-TRANSFER
redox biology
chemistry.chemical_classification
Flavin adenine dinucleotide
reactive oxygen species
Multidisciplinary
NADPH oxidase
biology
NADPH Oxidases
NOX
Biological Sciences
Transmembrane protein
Cell biology
Transmembrane domain
CHRONIC GRANULOMATOUS-DISEASE
030104 developmental biology
chemistry
DNA-DAMAGE
biology.protein
REACTIVE OXYGEN
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 114
- Issue :
- 26
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Science of the United States of America
- Accession number :
- edsair.doi.dedup.....df0ab45317d0bc95faf3aff3453a907f