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Structures of the neuronal and endothelial nitric oxide synthase heme domain with D-nitroarginine-containing dipeptide inhibitors bound.

Flinspach M, Li H, Jamal J, Yang W, Huang H, Silverman RB, Poulos TL
Biochemistry 43 5181-7 (2004)
Related entries: 1rs7, 1rs8, 1rs9

Cited: 17 times
EuropePMC logo PMID: 15122883

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-Arg(NO)2-NH(2) and D-Phe-D-Arg(NO)2-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 K(i) 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 alpha-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.

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Reviews citing this publication (1)

  1. Design of selective neuronal nitric oxide synthase inhibitors for the prevention and treatment of neurodegenerative diseases. Silverman RB. Acc Chem Res 42 439-451 (2009)

Articles citing this publication (14)

  1. Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase. Garcin ED, Arvai AS, Rosenfeld RJ, Kroeger MD, Crane BR, Andersson G, Andrews G, Hamley PJ, Mallinder PR, Nicholls DJ, St-Gallay SA, Tinker AC, Gensmantel NP, Mete A, Cheshire DR, Connolly S, Stuehr DJ, Aberg A, Wallace AV, Tainer JA, Getzoff ED. Nat Chem Biol 4 700-707 (2008)
  2. Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy. Ji H, Tan S, Igarashi J, Li H, Derrick M, Martásek P, Roman LJ, Vásquez-Vivar J, Poulos TL, Silverman RB. Ann Neurol 65 209-217 (2009)
  3. Discovery of highly potent and selective inhibitors of neuronal nitric oxide synthase by fragment hopping. Ji H, Li H, Martásek P, Roman LJ, Poulos TL, Silverman RB. J Med Chem 52 779-797 (2009)
  4. Structural studies of constitutive nitric oxide synthases with diatomic ligands bound. Li H, Igarashi J, Jamal J, Yang W, Poulos TL. J Biol Inorg Chem 11 753-768 (2006)
  5. Exploration of the active site of neuronal nitric oxide synthase by the design and synthesis of pyrrolidinomethyl 2-aminopyridine derivatives. Ji H, Delker SL, Li H, Martásek P, Roman LJ, Poulos TL, Silverman RB. J Med Chem 53 7804-7824 (2010)
  6. Recruitment of governing elements for electron transfer in the nitric oxide synthase family. Jáchymová M, Martásek P, Panda S, Roman LJ, Panda M, Shea TM, Ishimura Y, Kim JJ, Masters BS. Proc Natl Acad Sci U S A 102 15833-15838 (2005)
  7. Simplified 2-aminoquinoline-based scaffold for potent and selective neuronal nitric oxide synthase inhibition. Cinelli MA, Li H, Chreifi G, Martásek P, Roman LJ, Poulos TL, Silverman RB. J Med Chem 57 1513-1530 (2014)
  8. Crystal structures of constitutive nitric oxide synthases in complex with de novo designed inhibitors. Igarashi J, Li H, Jamal J, Ji H, Fang J, Lawton GR, Silverman RB, Poulos TL. J Med Chem 52 2060-2066 (2009)
  9. Selective inhibition of iNOS by benzyl- and dibenzyl derivatives of N-(3-aminobenzyl)acetamidine. Fantacuzzi M, Maccallini C, Lannutti F, Patruno A, Masella S, Pesce M, Speranza L, Ammazzalorso A, De Filippis B, Giampietro L, Re N, Amoroso R. ChemMedChem 6 1203-1206 (2011)
  10. Nitric oxide synthases activation and inhibition by metallacarborane-cluster-based isoform-specific affectors. Kaplánek R, Martásek P, Grüner B, Panda S, Rak J, Masters BS, Král V, Roman LJ. J Med Chem 55 9541-9548 (2012)
  11. Hydroxyl-terminated peptidomimetic inhibitors of neuronal nitric oxide synthase. Mbadugha BN, Seo J, Ji H, Martásek P, Roman LJ, Shea TM, Li H, Poulos TL, Silverman RB. Bioorg Med Chem 14 3681-3690 (2006)
  12. Hydroxyethylene isosteres of selective neuronal nitric oxide synthase inhibitors. Erdal EP, Martásek P, Roman LJ, Silverman RB. Bioorg Med Chem 15 6096-6108 (2007)
  13. Investigations on the role of π-π interactions and π-π networks in eNOS and nNOS proteins. Vaideeswaran S, Ramaiah S. Bioorg Chem 49 16-23 (2013)
  14. News [A novel strategy to design specific iNOS inhibitors]. Garcin E. Med Sci (Paris) 25 562-564 (2009)


Related citations provided by authors (1)

  1. The novel binding mode of N-alkyl-N'-hydroxyguanidine to neuronal nitric oxide synthase provides mechanistic insights into NO biosynthesis. Li H, Shimizu H, Flinspach ML, Jamal J, Yang W, Xian M, Cai T, Wen EZ, Jia Q, Wang PG, Poulos TL Biochemistry 41 13868-13875 (2002)

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