Structure of Nitric Oxide Synthase Oxygenase Dimer with Pterin and Substrate
1998; American Association for the Advancement of Science; Volume: 279; Issue: 5359 Linguagem: Inglês
10.1126/science.279.5359.2121
ISSN1095-9203
AutoresBrian R. Crane, A.S. Arvai, Dipak Ghosh, Chaoqun Wu, Elizabeth D. Getzoff, Dennis J. Stuehr, John A. Tainer,
Tópico(s)Eicosanoids and Hypertension Pharmacology
ResumoCrystal 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.
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