Mechanism of inhibition of bovine F 1 -ATPase by resveratrol and related polyphenols

Abstract

The structures of F ₁ -ATPase from bovine heart mitochondria inhibited with the dietary phytopolyphenol, resveratrol, and with the related polyphenols quercetin and piceatannol have been determined at 2.3-, 2.4- and 2.7-Å resolution, respectively. The inhibitors bind to a common site in the inside surface of an annulus made from loops in the three α- and three β-subunits beneath the “crown” of β-strands in their N-terminal domains. This region of F ₁ -ATPase forms a bearing to allow the rotation of the tip of the γ-subunit inside the annulus during catalysis. The binding site is a hydrophobic pocket between the C-terminal tip of the γ-subunit and the β _TP subunit, and the inhibitors are bound via H-bonds mostly to their hydroxyl moieties mediated by bound water molecules and by hydrophobic interactions. There are no equivalent sites between the γ-subunit and either the β _DP or the β _E subunit. The inhibitors probably prevent both the synthetic and hydrolytic activities of the enzyme by blocking both senses of rotation of the γ-subunit. The beneficial effects of dietary resveratrol may derive in part by preventing mitochondrial ATP synthesis in tumor cells, thereby inducing apoptosis.