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Molecular simulations enlighten the binding mode of quercetin to lipoxygenase‐3
Author(s) -
Fiorucci Sébastien,
Golebiowski Jérôme,
CabrolBass Daniel,
Antonczak Serge
Publication year - 2008
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.22179
Subject(s) - quercetin , steric effects , chemistry , flavonoid , substrate (aquarium) , enzyme , stereochemistry , molecular dynamics , dioxygenase , active site , biochemistry , computational chemistry , biology , antioxidant , ecology
Inhibition of lipoxygenases (LOXs) by flavonoid compounds is now well documented, but the description of the associated mechanism remains controversial due to a lack of information at the molecular level. For instance, X‐ray determination of quercetin/LOX‐3 system has led to a structure where the enzyme was cocrystallized with a degradation product of the substrate, which rendered the interpretation of the reported interactions between this flavonoid compound and the enzyme difficult. Molecular modeling simulations can in principle allow obtaining precious insights that could fill this lack of structural information. Thus, in this study, we have investigated various binding modes of quercetin to LOX‐3 enzyme in order to understand the first step of the inhibition process, that is the association of the two entities. Molecular dynamics simulations and free energy calculations suggest that quercetin binds the metal center via its 3‐hydroxychromone function. Moreover, enzyme/substrate interactions within the cavity impose steric hindrances to quercetin that may activate a direct dioxygen addition on the substrate. Proteins 2008;73:290–298. © 2008 Wiley‐Liss, Inc.