Structural characterization of nitric oxide synthase isoforms reveals striking active-site conservation.
Fischmann TO,
Hruza A,
Niu XD,
Fossetta JD,
Lunn CA,
Dolphin E,
Prongay AJ,
Reichert P,
Lundell DJ,
Narula SK,
Weber PC.
Structural Chemistry Department, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. thierry.fischmann@spcorp.com
Crystal structures of human endothelial nitric oxide synthase (eNOS) and human inducible NOS (iNOS) catalytic domains were solved in complex with the arginine substrate and an inhibitor S-ethylisothiourea (SEITU), respectively. The small molecules bind in a narrow cleft within the larger active-site cavity containing heme and tetrahydrobiopterin. Both are hydrogen-bonded to a conserved glutamate (eNOS E361, iNOS E377). The active-site residues of iNOS and eNOS are nearly identical. Nevertheless, structural comparisons provide a basis for design of isozyme-selective inhibitors. The high-resolution, refined structures of eNOS (2.4 A resolution) and iNOS (2.25 A resolution) reveal an unexpected structural zinc situated at the intermolecular interface and coordinated by four cysteines, two from each monomer.
PMID: 10074942 [PubMed - indexed for MEDLINE]