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

Article Details

Citation

Raman CS, Li H, Martasek P, Southan G, Masters BS, Poulos TL

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

Biochemistry. 2001 Nov 13;40(45):13448-55.

PubMed ID
11695891 [ View in PubMed
]
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 A 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.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
NitroarginineNitric oxide synthase, endothelialProteinHumans
Unknown
Not AvailableDetails