Structure of Nitric Oxide Synthase Oxygenase Dimer with Pterin and Substrate

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Abstract
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° 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.