title: Structures of human constitutive nitric oxide synthases.
abstract: Mammals produce three isoforms of nitric oxide synthase (NOS): neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS). The overproduction of NO by nNOS is associated with a number of neurodegenerative disorders; therefore, a desirable therapeutic goal is the design of drugs that target nNOS but not the other isoforms. Crystallography, coupled with computational approaches and medicinal chemistry, has played a critical role in developing highly selective nNOS inhibitors that exhibit exceptional neuroprotective properties. For historic reasons, crystallography has focused on rat nNOS and bovine eNOS because these were available in high quality; thus, their structures have been used in structure-activity-relationship studies. Although these constitutive NOSs share more than 90% sequence identity across mammalian species for each NOS isoform, inhibitor-binding studies revealed that subtle differences near the heme active site in the same NOS isoform across species still impact enzyme-inhibitor interactions. Therefore, structures of the human constitutive NOSs are indispensible. Here, the first structure of human neuronal NOS at 2.03 Å resolution is reported and a different crystal form of human endothelial NOS is reported at 1.73 Å resolution.
authors.affiliation: Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences and Chemistry, University of California, Irvine, 517 Bison Avenue, Irvine, CA 92697-3900, USA.
authors.forename: Huiying
authors.initials: H
authors.lastname: Li
authors.affiliation: Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences and Chemistry, University of California, Irvine, 517 Bison Avenue, Irvine, CA 92697-3900, USA.
authors.forename: Joumana
authors.initials: J
authors.lastname: Jamal
authors.affiliation: Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences and Chemistry, University of California, Irvine, 517 Bison Avenue, Irvine, CA 92697-3900, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: Plaza
authors.affiliation: Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences and Chemistry, University of California, Irvine, 517 Bison Avenue, Irvine, CA 92697-3900, USA.
authors.forename: Stephanie Hai
authors.initials: SH
authors.lastname: Pineda
authors.affiliation: Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences and Chemistry, University of California, Irvine, 517 Bison Avenue, Irvine, CA 92697-3900, USA.
authors.forename: Georges
authors.initials: G
authors.lastname: Chreifi
authors.affiliation: Department of Chemistry and Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Jing
authors.affiliation: Department of Chemistry and Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA.
authors.forename: Maris A
authors.initials: MA
authors.lastname: Cinelli
authors.affiliation: Department of Chemistry and Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
authors.affiliation: Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences and Chemistry, University of California, Irvine, 517 Bison Avenue, Irvine, CA 92697-3900, USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Poulos
mesh_terms: D000631:Aminopyridines / Q000737:chemistry; D000818:Animals; D020134:Catalytic Domain; D002417:Cattle; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry; D006418:Heme / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011759:Pyrrolidines / Q000737:chemistry; D051381:Rats
chemical_list: D000631:Aminopyridines; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D006418:Heme; C496320:NOS1 protein, human; C496314:NOS3 protein, human; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III
keywords: nitric oxide synthase