Unsymmetrical binding modes of the HOPNO inhibitor of tyrosinase: from model complexes to the enzyme.
The deciphering of the binding mode of tyrosinase (Ty) inhibitors is essential to understand how to regulate the tyrosinase activity. In this paper, by combining experimental and theoretical methods, we studied an unsymmetrical tyrosinase functional model and its interaction with 2-hydroxypyridine-N-oxide (HOPNO), a new and efficient competitive inhibitor for bacterial Ty. The tyrosinase model was a dinuclear copper complex bridged by a chelated ring with two different complexing arms (namely (bis(2-ethylpyridyl)amino)methyl and (bis(2-methylpyridyl)amino)methyl). The geometrical asymmetry of the complex induces an unsymmetrical binding of HOPNO. Comparisons have been made with the binding modes obtained on similar symmetrical complexes. Finally, by using quantum mechanics/molecular mechanics (QM/MM) calculations, we studied the binding mode in tyrosinase from a bacterial source. A new unsymmetrical binding mode was obtained, which was linked to the second coordination sphere of the enzyme.
Département de Chimie Moléculaire, Equipes CIRe et Chimie Théorique, Université J. Fourier, UMR-CNRS 5250, ICMG FR-2607, BP 53, 38041, Grenoble, Cedex 09, France.
Constance
C
Bochot
Elisabeth
E
Favre
Carole
C
Dubois
Benoit
B
Baptiste
Luigi
L
Bubacco
Pierre-Alain
PA
Carrupt
Gisèle
G
Gellon
Renaud
R
Hardré
Dominique
D
Luneau
Yohann
Y
Moreau
Alessandra
A
Nurisso
Marius
M
Réglier
Guy
G
Serratrice
Catherine
C
Belle
Hélène
H
Jamet
D001665:Binding Sites; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011789:Quantum Theory; D013329:Structure-Activity Relationship
C547041:2-hydroxypyridine-N-oxide; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D011725:Pyridines; D014442:Monophenol Monooxygenase