The structure of nitric oxide synthase oxygenase domain and inhibitor complexes.

TLDR: 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.

Abstract: The nitric oxide synthase oxygenase domain (NOS_(ox)) oxidizes arginine to synthesize the cellular signal and defensive cytotoxin nitric oxide (NO). Crystal structures determined for cytokine-inducible NOS_(ox) reveal an unusual fold and heme environment for stabilization of activated oxygen intermediates key for catalysis. A winged β sheet engenders a curved α-β 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 O_2- and polarL-arginine–binding sites occupied by imidazole and aminoguanidine, respectively, provide a template for designing dual-function inhibitors and imply substrate-assisted catalysis.