Structural basis for dipeptide amide isoform-selective inhibition of neuronal nitric oxide synthase |
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Authors: | Flinspach Mack L Li Huiying Jamal Joumana Yang Weiping Huang Hui Hah Jung-Mi Gómez-Vidal José Antonio Litzinger Elizabeth A Silverman Richard B Poulos Thomas L |
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Institution: | Department of Molecular Biology and Biochemistry and the Program in Macromolecular Structure, University of California, Irvine, California 92697-3900, USA. |
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Abstract: | Three nitric oxide synthase (NOS) isoforms, eNOS, nNOS and iNOS, generate nitric oxide (NO) crucial to the cardiovascular, nervous and host defense systems, respectively. Development of isoform-selective NOS inhibitors is of considerable therapeutic importance. Crystal structures of nNOS-selective dipeptide inhibitors in complex with both nNOS and eNOS were solved and the inhibitors were found to adopt a curled conformation in nNOS but an extended conformation in eNOS. We hypothesized that a single-residue difference in the active site, Asp597 (nNOS) versus Asn368 (eNOS), is responsible for the favored binding in nNOS. In the D597N nNOS mutant crystal structure, a bound inhibitor switches to the extended conformation and its inhibition of nNOS decreases >200-fold. Therefore, a single-residue difference is responsible for more than two orders of magnitude selectivity in inhibition of nNOS over eNOS by L-N(omega)-nitroarginine-containing dipeptide inhibitors. |
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