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Published March 27, 1998 | public
Journal Article

Structure of Nitric Oxide Synthase Oxygenase Dimer with Pterin and Substrate

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.

Additional Information

© 1998 American Association for the Advancement of Science. Received 16 December 1997; accepted 11 February 1998. We thank C. D. Putnam, A. M. Bilwes, J. Skinner, and R. M. Sweet for help with data collection, NSLS and SSRL for use of data collection facilities, and J. R. Winkler and H. B. Gray for access to Beckman Institute resources. We also thank C. Mol, T. Macke, A. M. Bilwes, C. D. Putnam, M. Marletta, and B. S. S. Masters for helpful discussions. Supported by NIH grant HL58883 and a Helen Hay Whitney Fellowship to B.R.C. D.J.S. is an Established Investigator of the American Heart Association. The Protein Data Base codes are 1nod for H_4B-ARG, 2nod for H_4B-H_2O, and 3nod for H_4B-SCIT.

Additional details

Created:
August 19, 2023
Modified:
October 18, 2023