Structural characterization of nitric oxide synthase isoforms reveals striking active-site conservation |
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Authors: | Fischmann T O Hruza A Niu X D Fossetta J D Lunn C A Dolphin E Prongay A J Reichert P Lundell D J Narula S K Weber P C |
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Affiliation: | Structural Chemistry Department, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. thierry.fischmann@spcorp.com |
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Abstract: | 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. |
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