HEAVY ATOM SCREENING FOR OXYGEN DOMAIN OF INDUCIBLE NITRIC OXIDE SYNTHASE

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The metalloenzyme nitric oxide synthase (NOS) regulates nitric oxide (NO) synthesis and thereby its biological activity. NO has a dual role as 1) a diffusible, biological messenger for neurotransimission, long-term potentiatltion, platelet aggregation, and blood pressure regulation and 2) a cytotoxic agent for defense against tumor cells and intracellulare parasites. NOS enzymes, found in inducible (iNOS), constitutive endothelial (eNOS), and constitutive neuronal (nNOS) isoforms acheive their important biological function by adopting an intriguing calcium-regulated mechanism and incorporating a unique assembly of five cofactors: heme, tetrahydrobiopterin, contained in an oxygenase domain, and FMN, FAD and NADPH contained in a reductase domain. We have obtained crystals of the murine iNOS oxygenase domain that diffract to 2.5 angstrom resolution with a synchrotron source at 100 K. Cysteine mutants of iNOSox, designed to facilitate derivatization, are being produced and one has already been crystallized. An atomic structure of iNOSox should lend much insight to the understanding of a unique catalytic mechanism and potentially the physiological role of NOS and NO.