THE STRUCTURE OF NITRIC-OXIDE SYNTHASE OXYGENASE DOMAIN AND INHIBITORCOMPLEXES

The nitric oxide synthase oxygenase domain (NOSox) oxidizes arginine t o synthesize the cellular signal and defensive cytotoxin nitric oxide (NO). Crystal structures determined for cytokine-inducible NOSox revea l 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 h eme clasped in the palm. The location of exposed hydrophobic residues and the results of mutational analysis place the dimer interface adjac ent to the heme-binding pocket. Juxtaposed hydrophobic O-2- and polar L-arginine-binding sites occupied by imidazole and aminoguanidine, res pectively, provide a template for designing dual-function inhibitors a nd imply substrate-assisted catalysis.