Mapping the active site polarity in structures of endothelial nitric oxide synthase heme domain complexed with isothioureas.
Analyzing the active site topology and plasticity of nitric oxide synthase (NOS) and understanding enzyme-drug interactions are crucial for the development of potent, isoform-selective NOS inhibitors. A small hydrophobic pocket in the active site is identified in the bovine eNOS heme domain structures complexed with potent isothiourea inhibitors: seleno analogue of S-ethyl-isothiourea, S-isopropyl-isothiourea, and 2-aminothiazoline, respectively. These structures reveal the importance of nonpolar van der Waals contacts in addition to the well-known hydrogen bonding interactions between inhibitor and enzyme. The scaffold of a potent NOS inhibitor should be capable of donating hydrogen bonds to as well as making nonpolar contacts with amino acids in the NOS active site.
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Department of Molecular Biology & Biochemistry and Physiology & Biophysics and Program in Macromolecular Structure, University of California, Irvine 92697-3900, USA.
Raman
C S
CS
Martásek
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P
Král
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V
Masters
B S
BS
Poulos
T L
TL
D001665:Binding Sites; D018360:Crystallography, X-Ray; D004727:Endothelium / Q000201:enzymology*; D006418:Heme / Q000378:metabolism*; D006801:Humans; D007550:Isothiuronium / Q000031:analogs & derivatives* / Q000737:chemistry; D007700:Kinetics; D008958:Models, Molecular; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013844:Thiazoles / Q000737:chemistry; D013890:Thiourea / Q000031:analogs & derivatives / Q000737:chemistry
C421486:S-isopropylthiourea; D013844:Thiazoles; D007550:Isothiuronium; C007687:etiron; D006418:Heme; C031363:2-aminothiazoline; D019001:Nitric Oxide Synthase; D013890:Thiourea