Abstract
The nitric oxide synthase oxygenase domain (NOSox) oxidizes arginine to synthesize the cellular signal and defensive cytotoxin nitric oxide (NO). Crystal structures determined for cytokine-inducible NOSox reveal an unusual fold and heme environment for stabilization of activated oxygen intermediates key for catalysis. A winged beta sheet engenders a curved alpha-beta domain resembling a baseball catcher's mitt with heme clasped in the palm. The location of exposed hydrophobic residues and the results of mutational analysis place the dimer interface adjacent to the heme-binding pocket. Juxtaposed hydrophobic O2- and polar L-arginine-binding sites occupied by imidazole and aminoguanidine, respectively, provide a template for designing dual-function inhibitors and imply substrate-assisted catalysis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Arginine / chemistry
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Arginine / metabolism
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Binding Sites
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Biopterins / analogs & derivatives
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Biopterins / metabolism
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Caenorhabditis elegans Proteins*
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Catalysis
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Crystallography, X-Ray
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Dimerization
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Enzyme Induction
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Enzyme Inhibitors / metabolism
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Guanidines / metabolism
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Heme / chemistry
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Homeodomain Proteins / chemistry
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Homeodomain Proteins / genetics*
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Homeodomain Proteins / physiology
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Hydrogen Bonding
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Imidazoles / metabolism
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / chemistry*
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Isoenzymes / metabolism
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Models, Molecular
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Molecular Sequence Data
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Nitric Oxide Synthase / antagonists & inhibitors
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Nitric Oxide Synthase / chemistry*
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Nitric Oxide Synthase / metabolism
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Oxidation-Reduction
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Oxygen / metabolism
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Oxygenases / chemistry
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Oxygenases / metabolism
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Protein Conformation*
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Protein Folding
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Protein Structure, Secondary
Substances
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Caenorhabditis elegans Proteins
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Enzyme Inhibitors
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Guanidines
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Homeodomain Proteins
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Imidazoles
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Isoenzymes
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lin-39 protein, C elegans
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Biopterins
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Heme
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imidazole
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Arginine
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Oxygenases
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Nitric Oxide Synthase
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sapropterin
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Oxygen
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pimagedine