Structures of the Neuronal and Endothelial Nitric Oxide Synthase Heme Domain with D-Nitroarginine-Containing Dipeptide Inhibitors Bound

Mack Flinspach, Huiying Li, Joumana Jamal, Weiping Yang, Hui Huang, Richard B. Silverman, Thomas L. Poulos*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

In a continuing effort to unravel the structural basis for isoform-selective inhibition of nitric oxide synthase (NOS) by various inhibitors, we have determined the crystal structures of the nNOS and eNOS heme domain bound with two D-nitroarginine-containing dipeptide inhibitors, D-Lys-D-ArgNO2-NH2 and D-Phe-D-ArgNO2-NH 2. These two dipeptide inhibitors exhibit similar binding modes in the two constitutive NOS isozymes, which is consistent with the similar binding affinities for the two isoforms as determined by Ki measurements. The D-nitroarginine-containing dipeptide inhibitors are not distinguished by the amino acid difference between nNOS and eNOS (Asp 597 and Asn 368, respectively) which is key in controlling isoform selection for nNOS over eNOS observed for the L-nitroarginine-containing dipeptide inhibitors reported previously [Flinspach, M., et al. (2004) Nat. Struct. Mol. Biol. 11, 54-59]. The lack of a free α-amino group on the D-nitroarginine moiety makes the dipeptide inhibitor steer away from the amino acid binding pocket near the active site. This allows the inhibitor to extend into the solvent-accessible channel farther away from the active site, which enables the inhibitors to explore new isoform-specific enzyme-inhibitor interactions. This might be the structural basis for why these D-nitroarginine-containing inhibitors are selective for nNOS (or eNOS) over iNOS.

Original languageEnglish (US)
Pages (from-to)5181-5187
Number of pages7
JournalBiochemistry
Volume43
Issue number18
DOIs
StatePublished - May 11 2004

ASJC Scopus subject areas

  • Biochemistry

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