Nature Structural Biology
6, 233 - 242 (1999)
doi:10.1038/6675
Structural characterization of nitric oxide synthase isoforms reveals
striking active-site conservationThierry O. Fischmann1, Alan Hruza1, Xiao Da Niu2, James D. Fossetta2, Charles A. Lunn2, Edward Dolphin2, Andrew J. Prongay1, Paul Reichert1, Daniel J. Lundell2, Satwant K. Narula2
& Patricia C. Weber11
Structural Chemistry Department, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. 2
Immunology Department, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA.
Correspondence should be addressed to Thierry O. Fischmann thierry.fischmann@spcorp.comCrystal 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 Å resolution) and iNOS (2.25 Å resolution) reveal
an unexpected structural zinc situated at the intermolecular interface and
coordinated by four cysteines, two from each monomer.
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