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Role of zinc in isoform-selective inhibitor binding to neuronal nitric oxide synthase .

Delker SL, Xue F, Li H, Jamal J, Silverman RB, Poulos TL
Biochemistry 49 10803-10 (2010)

Cited: 22 times
EuropePMC logo PMID: 21138269

Abstract

In previous studies [Delker, S. L., et al. (2010), J. Am. Chem. Soc. 132, 5437-5442], we determined the crystal structures of neuronal nitric oxide synthase (nNOS) in complex with nNOS-selective chiral pyrrolidine inhibitors, designed to have an aminopyridine group bound over the heme where it can electrostatically interact with the conserved active site Glu residue. However, in addition to the expected binding mode with the (S,S)-cis inhibitors, an unexpected "flipped" orientation was observed for the (R,R)-cis enantiomers. In the flipped mode, the aminopyridine extends out of the active site where it interacts with one heme propionate. This prompted us to design and synthesize symmetric "double-headed" inhibitors with an aminopyridine at each end of a bridging ring structure [Xue, F., Delker, S. L., Li, H., Fang, J., Jamal, J., Martásek, P., Roman, L. J., Poulos, T. L., and Silverman, R. B. Symmetric double-headed aminopyridines, a novel strategy for potent and membrane-permeable inhibitors of neuronal nitric oxide synthase. J. Med. Chem. (submitted for publication)]. One aminopyridine should interact with the active site Glu and the other with the heme propionate. Crystal structures of these double-headed aminopyridine inhibitors in complexes with nNOS show unexpected and significant protein and heme conformational changes induced by inhibitor binding that result in removal of the tetrahydrobiopterin (H(4)B) cofactor and creation of a new Zn(2+) site. These changes are due to binding of a second inhibitor molecule that results in the displacement of H(4)B and the placement of the inhibitor pyridine group in position to serve as a Zn(2+) ligand together with Asp, His, and a chloride ion. Binding of the second inhibitor molecule and generation of the Zn(2+) site do not occur in eNOS. Structural requirements for creation of the new Zn(2+) site in nNOS were analyzed in detail. These observations open the way for the potential design of novel inhibitors selective for nNOS.

Articles - 3n62 mentioned but not cited (1)

  1. Role of zinc in isoform-selective inhibitor binding to neuronal nitric oxide synthase . Delker SL, Xue F, Li H, Jamal J, Silverman RB, Poulos TL. Biochemistry 49 10803-10810 (2010)


Reviews citing this publication (4)

  1. Development of nitric oxide synthase inhibitors for neurodegeneration and neuropathic pain. Mukherjee P, Cinelli MA, Kang S, Silverman RB. Chem Soc Rev 43 6814-6838 (2014)
  2. Role of neuronal nitric oxide synthase on cardiovascular functions in physiological and pathophysiological states. Ally A, Powell I, Ally MM, Chaitoff K, Nauli SM. Nitric Oxide 102 52-73 (2020)
  3. Nitric oxide synthase and structure-based inhibitor design. Poulos TL, Li H. Nitric Oxide 63 68-77 (2017)
  4. Recent advances toward improving the bioavailability of neuronal nitric oxide synthase inhibitors. Huang H, Silverman RB. Curr Top Med Chem 13 803-812 (2013)

Articles citing this publication (17)

  1. Structural basis for isoform-selective inhibition in nitric oxide synthase. Poulos TL, Li H. Acc Chem Res 46 390-398 (2013)
  2. Symmetric double-headed aminopyridines, a novel strategy for potent and membrane-permeable inhibitors of neuronal nitric oxide synthase. Xue F, Fang J, Delker SL, Li H, Martásek P, Roman LJ, Poulos TL, Silverman RB. J Med Chem 54 2039-2048 (2011)
  3. Nitric Oxide Synthase as a Target for Methicillin-Resistant Staphylococcus aureus. Holden JK, Kang S, Beasley FC, Cinelli MA, Li H, Roy SG, Dejam D, Edinger AL, Nizet V, Silverman RB, Poulos TL. Chem Biol 22 785-792 (2015)
  4. Sodium fluoride induces renal inflammatory responses by activating NF-κB signaling pathway and reducing anti-inflammatory cytokine expression in mice. Luo Q, Cui H, Deng H, Kuang P, Liu H, Lu Y, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L. Oncotarget 8 80192-80207 (2017)
  5. Structure-based design of bacterial nitric oxide synthase inhibitors. Holden JK, Kang S, Hollingsworth SA, Li H, Lim N, Chen S, Huang H, Xue F, Tang W, Silverman RB, Poulos TL. J Med Chem 58 994-1004 (2015)
  6. Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase. Cinelli MA, Li H, Pensa AV, Kang S, Roman LJ, Martásek P, Poulos TL, Silverman RB. J Med Chem 58 8694-8712 (2015)
  7. Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors. Cinelli MA, Li H, Chreifi G, Poulos TL, Silverman RB. J Med Chem 60 3958-3978 (2017)
  8. The mobility of a conserved tyrosine residue controls isoform-dependent enzyme-inhibitor interactions in nitric oxide synthases. Li H, Jamal J, Delker S, Plaza C, Ji H, Jing Q, Huang H, Kang S, Silverman RB, Poulos TL. Biochemistry 53 5272-5279 (2014)
  9. Cyclopropyl- and methyl-containing inhibitors of neuronal nitric oxide synthase. Li H, Xue F, Kraus JM, Ji H, Labby KJ, Mataka J, Delker SL, Martásek P, Roman LJ, Poulos TL, Silverman RB. Bioorg Med Chem 21 1333-1343 (2013)
  10. Regulation of LPS-induced mRNA expression of pro-inflammatory cytokines via alteration of NF-κB activity in mouse peritoneal macrophages exposed to fluoride. Tian Y, Huo M, Li G, Li Y, Wang J. Chemosphere 161 89-95 (2016)
  11. Modification of rat model of sciatica induced by lumber disc herniation and the anti-inflammatory effect of osthole given by epidural catheterization. Wei M, Mo SL, Nabar NR, Chen Y, Zhang JJ, He QL, Zou XN, Liu XG, Sun LB, Zhou SF. Pharmacology 90 251-263 (2012)
  12. Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2-Aminopyridine-Based Scaffold with a Pyridine Linker. Wang HY, Qin Y, Li H, Roman LJ, Martásek P, Poulos TL, Silverman RB. J Med Chem 59 4913-4925 (2016)
  13. Electrostatic Control of Isoform Selective Inhibitor Binding in Nitric Oxide Synthase. Li H, Wang HY, Kang S, Silverman RB, Poulos TL. Biochemistry 55 3702-3707 (2016)
  14. Optimization of Blood-Brain Barrier Permeability with Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibitors Having a 2-Aminopyridine Scaffold. Do HT, Li H, Chreifi G, Poulos TL, Silverman RB. J Med Chem 62 2690-2707 (2019)
  15. First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate. Cinelli MA, Reidl CT, Li H, Chreifi G, Poulos TL, Silverman RB. J Med Chem 63 4528-4554 (2020)
  16. Inhibitor Bound Crystal Structures of Bacterial Nitric Oxide Synthase. Holden JK, Dejam D, Lewis MC, Huang H, Kang S, Jing Q, Xue F, Silverman RB, Poulos TL. Biochemistry 54 4075-4082 (2015)
  17. Inhibition of inducible nitric oxide production by Caryota urens and its active constituents umbelliferone and rutin. Balaji S, Kavasseri Ganesan K. J Ayurveda Integr Med 12 369-372 (2021)


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