Crystal structure of nitric oxide synthase bound to nitro indazole reveals a novel inactivation mechanism

Academic Article

Abstract

  • Nitric oxide is generated under normal and pathophysiological conditions by three distinct isoforms of nitric oxide synthase (NOS). A small-molecule inhibitor of NOS (3-Br-7-nitroindazole, 7-NIBr) is profoundly neuroprotective in mouse models of stroke and Parkinson's disease. We report the crystal structure of the catalytic heme domain of endothelial NOS complexed with 7-NIBr at 1.65 Å resolution. Critical to the binding of 7-NIBr at the substrate site is the adoption by eNOS of an altered conformation, in which a key glutamate residue swings out toward one of the heme propionate groups. Perturbation of the heme propionate ensues and eliminates the cofactor tetrahydrobiopterin-heme interaction. We also present three crystal structures that reveal how alterations at the substrate site facilitate 7-NIBr and structurally dissimilar ligands to occupy the cofactor site.
  • Authors

    Published In

  • Biochemistry  Journal
  • Digital Object Identifier (doi)

    Author List

  • Raman CS; Li H; Martásek P; Southan G; Masters BSS; Poulos TL
  • Start Page

  • 13448
  • End Page

  • 13455
  • Volume

  • 40
  • Issue

  • 45