Download MendeleyCrystal structure of nitric oxide synthase bound to nitro indazole reveals a novel inactivation mechanism.
Raman, C.S., Li, H., Martasek, P., Southan, G., Masters, B.S., Poulos, T.L.(2001) Biochemistry 40: 13448-13455
- PubMed: 11695891
- DOI: https://doi.org/10.1021/bi010957u
- Primary Citation of Related Structures:
1D0C, 1D0O, 1DM6, 1ED5, 1FOJ, 8NSE - 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.
Organizational Affiliation:
Department of Molecular Biology & Biochemistry, University of California, Irvine, California 92697, USA. [email protected]
