title: Structural basis for the specificity of the nitric-oxide synthase inhibitors W1400 and Nomega-propyl-L-Arg for the inducible and neuronal isoforms.
abstract: The high level of amino acid conservation and structural similarity in the immediate vicinity of the substrate binding sites of the oxygenase domains of the nitric-oxide synthase (NOS) isoforms (eNOSoxy, iNOSoxy, and nNOSoxy) make the interpretation of the structural basis of inhibitor isoform specificity a challenge and provide few clues for the design of new selective compounds. Crystal structures of iNOSoxy and nNOSoxy complexed with the inhibitors W1400 and Nomega-propyl-l-arginine provide a rationale for their isoform specificity. It involves differences outside the immediate active site as well as a conformational flexibility in the active site that allows the adoption of distinct conformations in response to interactions with the inhibitors. This flexibility is determined by isoform-specific residues outside the active site.
authors.affiliation: Max Planck Institut für Molekulare Physiologie, Abteilung Biophysikalische Chemie, Otto Hahn Strasse 11, 44227 Dortmund, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Fedorov
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Hartmann
authors.forename: Dipak K
authors.initials: DK
authors.lastname: Ghosh
authors.forename: Ilme
authors.initials: I
authors.lastname: Schlichting
mesh_terms: D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D001667:Binding, Competitive; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D013379:Substrate Specificity
chemical_list: D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; C109599:N(omega)-propylarginine; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D001120:Arginine; D019001:Nitric Oxide Synthase