Structural basis for dipeptide amide isoform-selective inhibition of neuronal nitric oxide synthase

Mack L. Flinspach, Huiying Li, Joumana Jamal, Weiping Yang, Hui Huang, Jung Mi Hah, José Antonio Gómez-Vidal, Elizabeth A. Litzinger, Richard B. Silverman, Thomas L. Poulos*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

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-Nω-nitroarginine-containing dipeptide inhibitors.

Original languageEnglish (US)
Pages (from-to)54-59
Number of pages6
JournalNature Structural and Molecular Biology
Volume11
Issue number1
DOIs
StatePublished - Jan 2004

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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