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- Title
Structural basis for dipeptide amide isoform-selective inhibition of neuronal nitric oxide synthase.
- Authors
Flinspach, Mack K.; Huiying Li; Jamal, Joumana; Weiping Yang; Hui Huang; Jung-Mi Hah, Joumana; Gomez-Vidal, Jose Antonio; Litzinger, Elizabeth Al; Silverman, Richard B.; Poulos, Thomas L.
- 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?-nitroarginine-containing dipeptide inhibitors.
- Subjects
NITRIC-oxide synthases; NEURONS; PEPTIDES; CHEMICAL inhibitors; ENDOTHELIUM; MOLECULAR structure
- Publication
Nature Structural & Molecular Biology, 2004, Vol 11, Issue 1, p54
- ISSN
1545-9993
- Publication type
Article
- DOI
10.1038/nsmb704