The structure of nitric oxide synthase oxygenase domain and inhibitor complexes.
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.
Crane
B R
BR
Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Arvai
A S
AS
Gachhui
R
R
Wu
C
C
Ghosh
D K
DK
Getzoff
E D
ED
Stuehr
D J
DJ
Tainer
J A
JA
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
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