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Structure of Nitric Oxide Synthase Oxygenase Dimer with Pterin and Substrate

Crane, Brian R. and Arvai, Andrew S. and Ghosh, Dipak K. and Wu, Chaoqun and Getzoff, Elizabeth D. and Stuehr, Dennis J. and Tainer, John A. (1998) Structure of Nitric Oxide Synthase Oxygenase Dimer with Pterin and Substrate. Science, 279 (5359). pp. 2121-2126. ISSN 0036-8075. https://resolver.caltech.edu/CaltechAUTHORS:20141125-110847194

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1126/science.279.5359.2121DOIArticle
http://www.sciencemag.org/content/279/5359/2121PublisherArticle
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.
Funders:
Funding AgencyGrant Number
NIHHL58883
Helen Hay Whitney FoundationUNSPECIFIED
Issue or Number:5359
Record Number:CaltechAUTHORS:20141125-110847194
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20141125-110847194
Official Citation:Structure of Nitric Oxide Synthase Oxygenase Dimer with Pterin and Substrate Brian R. Crane, Andrew S. Arvai, Dipak K. Ghosh, Chaoqun Wu, Elizabeth D. Getzoff, Dennis J. Stuehr, and John A. Tainer Science 27 March 1998: 279 (5359), 2121-2126. [DOI:10.1126/science.279.5359.2121]
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:52145
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:25 Nov 2014 20:14
Last Modified:03 Oct 2019 07:39

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