1P6N : Bovine endothelial NOS heme domain with L-N(omega)-nitroarginine-(4R)-amino-L-proline amide bound

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



Experimental Technique/Method:X-RAY DIFFRACTION
Release Date:2004-01-13
Deposition Date:2003-04-29
Revision Date:2008-04-29#2011-07-13
Molecular Weight:96984.23
Macromolecule Type:Protein
Residue Count:834
Atom Site Count:6634

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.
Date made available2004

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