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Structural basis for the specificity of the nitric-oxide synthase inhibitors W1400 and Nomega-propyl-L-Arg for the inducible and neuronal isoforms

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Fedorov,  Roman
Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society;

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Hartmann,  Elisabeth
Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society;

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Schlichting,  Ilme
Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society;

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Citation

Fedorov, R., Hartmann, E., Ghosh, D. K., & Schlichting, I. (2003). Structural basis for the specificity of the nitric-oxide synthase inhibitors W1400 and Nomega-propyl-L-Arg for the inducible and neuronal isoforms. The Journal of Biological Chemistry, 278(46), 45818-45825. doi:10.1074/jbc.M306030200.


Cite as: https://hdl.handle.net/11858/00-001M-0000-0029-B1F0-1
Abstract
The high level of amino acid conservation and structural similarity in the immediate vicinity of the substrate binding sites of the oxygenase domains of the nitric-oxide synthase (NOS) isoforms (eNOSoxy, iNOSoxy, and nNOSoxy) make the interpretation of the structural basis of inhibitor isoform specificity a challenge and provide few clues for the design of new selective compounds. Crystal structures of iNOSoxy and nNOSoxy complexed with the inhibitors W1400 and Nomega-propyl-l-arginine provide a rationale for their isoform specificity. It involves differences outside the immediate active site as well as a conformational flexibility in the active site that allows the adoption of distinct conformations in response to interactions with the inhibitors. This flexibility is determined by isoform-specific residues outside the active site.