thiourea and sapropterin

Crystal structures of the murine cytokine-inducible nitric oxide synthase oxygenase dimer with active-center water molecules, the substrate L-arginine (L-Arg), or product analog thiocitrulline reveal how dimerization, cofactor tetrahydrobiopterin, and L-Arg binding complete the catalytic center for synthesis of the essential biological signal and cytotoxin nitric oxide. Pterin binding refolds the central interface region, recruits new structural elements, creates a 30 angstrom deep active-center channel, and causes a 35 degrees helical tilt to expose a heme edge and the adjacent residue tryptophan-366 for likely reductase domain interactions and caveolin inhibition. Heme propionate interactions with pterin and L-Arg suggest that pterin has electronic influences on heme-bound oxygen. L-Arginine binds to glutamic acid-371 and stacks with heme in an otherwise hydrophobic pocket to aid activation of heme-bound oxygen by direct proton donation and thereby differentiate the two chemical steps of nitric oxide synthesis.

Topics: Animals; Arginine; Binding Sites; Biopterins; Citrulline; Crystallography, X-Ray; Dimerization; Hydrogen Bonding; Isoenzymes; Ligands; Macrophages; Mice; Models, Molecular; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Protein Conformation; Protein Folding; Protein Structure, Secondary; Thiourea