8U86

Structural Basis of Human NOX5 Activation

Summary for 8U86

• Entry DOI: 10.2210/pdb8u86/pdb
• EMDB information: 42015
• Descriptor: NADPH oxidase 5, HEME B/C, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (7 entities in total)
• Functional Keywords: enzyme, oxidase, activation mechanism, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 170464.58

Authors

Cui, C.,Jiang, M.,Sun, J. (deposition date: 2023-09-15, release date: 2024-05-01, Last modification date: 2024-11-06)

Primary citation

Cui, C.,Jiang, M.,Jain, N.,Das, S.,Lo, Y.H.,Kermani, A.A.,Pipatpolkai, T.,Sun, J.
Structural basis of human NOX5 activation.
Nat Commun, 15:3994-3994, 2024

PubMed Abstract: NADPH oxidase 5 (NOX5) catalyzes the production of superoxide free radicals and regulates physiological processes from sperm motility to cardiac rhythm. Overexpression of NOX5 leads to cancers, diabetes, and cardiovascular diseases. NOX5 is activated by intracellular calcium signaling, but the underlying molecular mechanism of which - in particular, how calcium triggers electron transfer from NADPH to FAD - is still unclear. Here we capture motions of full-length human NOX5 upon calcium binding using single-particle cryogenic electron microscopy (cryo-EM). By combining biochemistry, mutagenesis analyses, and molecular dynamics (MD) simulations, we decode the molecular basis of NOX5 activation and electron transfer. We find that calcium binding to the EF-hand domain increases NADPH dynamics, permitting electron transfer between NADPH and FAD and superoxide production. Our structural findings also uncover a zinc-binding motif that is important for NOX5 stability and enzymatic activity, revealing modulation mechanisms of reactive oxygen species (ROS) production.

PubMed: 38734761
DOI: 10.1038/s41467-024-48467-y

Experimental method

ELECTRON MICROSCOPY (3.3 Å)