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

C. S. Raman, H. Li, P. Martásek, G. Southan, B. S.S. Masters, T. L. Poulos

Research output: Contribution to journalArticle

81 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)13448-13455
Number of pages8
JournalBiochemistry
Volume40
Issue number45
DOIs
StatePublished - Nov 13 2001

ASJC Scopus subject areas

  • Biochemistry

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    Raman, C. S., Li, H., Martásek, P., Southan, G., Masters, B. S. S., & Poulos, T. L. (2001). Crystal structure of nitric oxide synthase bound to nitro indazole reveals a novel inactivation mechanism. Biochemistry, 40(45), 13448-13455. https://doi.org/10.1021/bi010957u