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Science 27 March 1998:
Vol. 279. no. 5359, pp. 2121 - 2126
DOI: 10.1126/science.279.5359.2121
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Reports

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, dagger John A. Tainer dagger

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.

B. R. Crane, A. S. Arvai, E. D. Getzoff, J. A. Tainer, Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
D. K. Ghosh, C. Wu, D. J. Stuehr, Department of Immunology, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
*   Present address: Beckman Institute, California Institute of Technology, Pasadena, CA 91125, USA.

dagger    To whom correspondence should be addressed.

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Crucial Role of Lys423 in the Electron Transfer of Neuronal Nitric-oxide Synthase.
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Geminate Recombination of Nitric Oxide to Endothelial Nitric-oxide Synthase and Mechanistic Implications.
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Mutational Analysis of the Tetrahydrobiopterin-binding Site in Inducible Nitric-oxide Synthase.
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Enzymatic function of nitric oxide synthases.
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Signal transduction of eNOS activation.
I. Fleming and R. Busse (1999)
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J. Biol. Chem. 274, 17559-17566
   Abstract »    Full Text »    PDF »
Activation of Neuronal Nitric-oxide Synthase by the 5-Methyl Analog of Tetrahydrobiopterin. FUNCTIONAL EVIDENCE AGAINST REDUCTIVE OXYGEN ACTIVATION BY THE PTERIN COFACTOR.
C. Riethmuller, A. C. F. Gorren, E. Pitters, B. Hemmens, H.-J. Habisch, S. J. R. Heales, K. Schmidt, E. R. Werner, and B. Mayer (1999)
J. Biol. Chem. 274, 16047-16051
   Abstract »    Full Text »    PDF »
Zinc Content of Escherichia coli-expressed Constitutive Isoforms of Nitric-oxide Synthase. ENZYMATIC ACTIVITY AND EFFECT OF PTERIN.
R. T. Miller, P. Martasek, C. S. Raman, and B. S. S. Masters (1999)
J. Biol. Chem. 274, 14537-14540
   Abstract »    Full Text »    PDF »
Modulation of the Remote Heme Site Geometry of Recombinant Mouse Neuronal Nitric-oxide Synthase by the N-terminal Hook Region.
T. Iwasaki, H. Hori, Y. Hayashi, and T. Nishino (1999)
J. Biol. Chem. 274, 7705-7713
   Abstract »    Full Text »    PDF »
Neuronal Nitric-oxide Synthase Is Regulated by the hsp90-based Chaperone System in Vivo.
A. T. Bender, A. M. Silverstein, D. R. Demady, K. C. Kanelakis, S. Noguchi, W. B. Pratt, and Y. Osawa (1999)
J. Biol. Chem. 274, 1472-1478
   Abstract »    Full Text »    PDF »
Antifungal Imidazoles Block Assembly of Inducible NO Synthase into an Active Dimer.
N. Sennequier, D. Wolan, and D. J. Stuehr (1999)
J. Biol. Chem. 274, 930-938
   Abstract »    Full Text »    PDF »
Kalirin Inhibition of Inducible Nitric-oxide Synthase.
E. A. Ratovitski, M. R. Alam, R. A. Quick, A. McMillan, C. Bao, C. Kozlovsky, T. A. Hand, R. C. Johnson, R. E. Mains, B. A. Eipper, et al. (1999)
J. Biol. Chem. 274, 993-999
   Abstract »    Full Text »    PDF »
The C331A Mutant of Neuronal Nitric-Oxide Synthase Is Defective in Arginine Binding.
P. Martasek, R. T. Miller, Q. Liu, L. J. Roman, J. C. Salerno, C. T. Migita, C. S. Raman, S. S. Gross, M. Ikeda-Saito, and B. S. S. Masters (1998)
J. Biol. Chem. 273, 34799-34805
   Abstract »    Full Text »    PDF »
Effects of Asp-369 and Arg-372 Mutations on Heme Environment and Function in Human Endothelial Nitric-oxide Synthase.
P.-F. Chen, V. Berka, A.-L. Tsai, and K. K. Wu (1998)
J. Biol. Chem. 273, 34164-34170
   Abstract »    Full Text »    PDF »
Anti-pterins as Tools to Characterize the Function of Tetrahydrobiopterin in NO Synthase.
H. M. Bommel, A. Reif, L. G. Frohlich, A. Frey, H. Hofmann, D. M. Marecak, V. Groehn, P. Kotsonis, M. La, S. Koster, et al. (1998)
J. Biol. Chem. 273, 33142-33149
   Abstract »    Full Text »    PDF »
Protein Inhibitor of Neuronal Nitric-oxide Synthase, PIN, Binds to a 17-Amino Acid Residue Fragment of the Enzyme.
J.-S. Fan, Q. Zhang, M. Li, H. Tochio, T. Yamazaki, M. Shimizu, and M. Zhang (1998)
J. Biol. Chem. 273, 33472-33481
   Abstract »    Full Text »    PDF »
Nitric Oxide Synthase Structure and Electron Transfer.
P. R. O. de Montellano, C. Nishida, I. Rodriguez-Crespo, and N. Gerber (1998)
Drug Metab. Dispos. 26, 1185-1189
   Abstract »    Full Text »
Effects of transition metals on nitric oxide synthase catalysis.
J. M. Perry and M. A. Marletta (1998)
PNAS 95, 11101-11106
   Abstract »    Full Text »    PDF »
Domain Swapping in Inducible Nitric-oxide Synthase. ELECTRON TRANSFER OCCURS BETWEEN FLAVIN AND HEME GROUPS LOCATED ON ADJACENT SUBUNITS IN THE DIMER.
U. Siddhanta, A. Presta, B. Fan, D. Wolan, D. L. Rousseau, and D. J. Stuehr (1998)
J. Biol. Chem. 273, 18950-18958
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Aromatic Residues and Neighboring Arg414 in the (6R)-5,6,7,8-Tetrahydro-L-Biopterin Binding Site of Full-length Neuronal Nitric-oxide Synthase Are Crucial in Catalysis and Heme Reduction with NADPH.
I. Sagami, Y. Sato, S. Daff, and T. Shimizu (2000)
J. Biol. Chem. 275, 26150-26157
   Abstract »    Full Text »    PDF »
Molecular Basis for Hyperactivity in Tryptophan 409 Mutants of Neuronal NO Synthase.
S. Adak, Q. Wang, and D. J. Stuehr (2000)
J. Biol. Chem. 275, 17434-17439
   Abstract »    Full Text »    PDF »
The C Terminus of Mouse Macrophage Inducible Nitric-oxide Synthase Attenuates Electron Flow through the Flavin Domain.
L. J. Roman, R. T. Miller, M. A. de la Garza, J.-J. P. Kim, and B. S. Siler Masters (2000)
J. Biol. Chem. 275, 21914-21919
   Abstract »    Full Text »    PDF »
Mutations at Lysine 525 of Inducible Nitric-oxide Synthase Affect Its Ca2+-independent Activity.
S.-J. Lee, K. Beckingham, and J. T. Stull (2000)
J. Biol. Chem. 275, 36067-36072
   Abstract »    Full Text »    PDF »
Arginine Conversion to Nitroxide by Tetrahydrobiopterin-free Neuronal Nitric-oxide Synthase. IMPLICATIONS FOR MECHANISM.
S. Adak, Q. Wang, and D. J. Stuehr (2000)
J. Biol. Chem. 275, 33554-33561
   Abstract »    Full Text »    PDF »
The C Termini of Constitutive Nitric-oxide Synthases Control Electron Flow through the Flavin and Heme Domains and Affect Modulation by Calmodulin.
L. J. Roman, P. Martasek, R. T. Miller, D. E. Harris, M. A. de la Garza, T. M. Shea, J.-J. P. Kim, and B. S. S. Masters (2000)
J. Biol. Chem. 275, 29225-29232
   Abstract »    Full Text »    PDF »
Role of Bound Zinc in Dimer Stabilization but Not Enzyme Activity of Neuronal Nitric-oxide Synthase.
B. Hemmens, W. Goessler, K. Schmidt, and B. Mayer (2000)
J. Biol. Chem. 275, 35786-35791
   Abstract »    Full Text »    PDF »
Reconstitution of Pterin-free Inducible Nitric-oxide Synthase.
K. M. Rusche and M. A. Marletta (2001)
J. Biol. Chem. 276, 421-427
   Abstract »    Full Text »    PDF »
Rapid Kinetic Studies Link Tetrahydrobiopterin Radical Formation to Heme-dioxy Reduction and Arginine Hydroxylation in Inducible Nitric-oxide Synthase.
C.-C. Wei, Z.-Q. Wang, Q. Wang, A. L. Meade, C. Hemann, R. Hille, and D. J. Stuehr (2001)
J. Biol. Chem. 276, 315-319
   Abstract »    Full Text »    PDF »
Structural Basis for Pterin Antagonism in Nitric-oxide Synthase. DEVELOPMENT OF NOVEL 4-OXO-PTERIDINE ANTAGONISTS OF (6R)-5,6,7,8-TETRAHYDROBIOPTERIN.
P. Kotsonis, L. G. Frohlich, C. S. Raman, H. Li, M. Berg, R. Gerwig, V. Groehn, Y. Kang, N. Al-Masoudi, S. Taghavi-Moghadam, et al. (2001)
J. Biol. Chem. 276, 49133-49141
   Abstract »    Full Text »    PDF »


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