Structural basis for the specificity of the nitric-oxide synthase inhibitors W1400 and Nomega-propyl-L-Arg for the inducible and neuronal isoforms.
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.
Fedorov
Roman
R
Max Planck Institut für Molekulare Physiologie, Abteilung Biophysikalische Chemie, Otto Hahn Strasse 11, 44227 Dortmund, Germany.
Hartmann
Elisabeth
E
Ghosh
Dipak K
DK
Schlichting
Ilme
I
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
D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; C109599:N(omega)-propylarginine; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D001120:Arginine; D019001:Nitric Oxide Synthase