title: The structure of nitric oxide synthase oxygenase domain and inhibitor complexes.
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.
authors.affiliation: Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: B R
authors.initials: BR
authors.lastname: Crane
authors.forename: A S
authors.initials: AS
authors.lastname: Arvai
authors.forename: R
authors.initials: R
authors.lastname: Gachhui
authors.forename: C
authors.initials: C
authors.lastname: Wu
authors.forename: D K
authors.initials: DK
authors.lastname: Ghosh
authors.forename: E D
authors.initials: ED
authors.lastname: Getzoff
authors.forename: D J
authors.initials: DJ
authors.lastname: Stuehr
authors.forename: J A
authors.initials: JA
authors.lastname: Tainer
mesh_terms: D000595:Amino Acid Sequence; D001120:Arginine / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins; D002384:Catalysis; D018360:Crystallography, X-Ray; D019281:Dimerization; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000378:metabolism; D006146:Guanidines / Q000378:metabolism; D006418:Heme / Q000737:chemistry; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D010105:Oxygenases / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary
chemical_list: D029742:Caenorhabditis elegans Proteins; D004791:Enzyme Inhibitors; D006146:Guanidines; D018398:Homeodomain Proteins; D007093:Imidazoles; D007527:Isoenzymes; C108673:lin-39 protein, C elegans; D001708:Biopterins; D006418:Heme; C029899:imidazole; D001120:Arginine; D010105:Oxygenases; D019001:Nitric Oxide Synthase; C003402:sapropterin; D010100:Oxygen; C004479:pimagedine