title: Mapping the active site polarity in structures of endothelial nitric oxide synthase heme domain complexed with isothioureas.
abstract: 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.
authors.affiliation: Department of Molecular Biology & Biochemistry and Physiology & Biophysics and Program in Macromolecular Structure, University of California, Irvine 92697-3900, USA.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.forename: C S
authors.initials: CS
authors.lastname: Raman
authors.forename: P
authors.initials: P
authors.lastname: Martásek
authors.forename: V
authors.initials: V
authors.lastname: Král
authors.forename: B S
authors.initials: BS
authors.lastname: Masters
authors.forename: T L
authors.initials: TL
authors.lastname: Poulos
mesh_terms: 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
chemical_list: C421486:S-isopropylthiourea; D013844:Thiazoles; D007550:Isothiuronium; C007687:etiron; D006418:Heme; C031363:2-aminothiazoline; D019001:Nitric Oxide Synthase; D013890:Thiourea