Mechanism of inhibition of bovine [F.sub.1]-ATPase by resveratrol and related polyphenols

The structures of [F.sub.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-[Angstrom] resolution, respectively. The inhibitors bind to a common site in the inside surface of an annulus made from loops in the three [alpha]- and three [beta]-subunits beneath the 'crown' of [beta]-strands in their N-terminal domains. This region of [F.sub.1]-ATPase forms a bearing to allow the rotation of the tip of the [gamma]-subunit inside the annulus during catalysis. The binding site is a hydrophobic pocket between the C-terminal tip of the [gamma]-subunit and the [[beta].sub.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 [gamma]-subunit and either the [[beta].sub.DP] or the [[beta].sub.E] subunit. The inhibitors probably prevent both the synthetic and hydrolytic activities of the enzyme by blocking both senses of rotation of the [gamma]-subunit. The beneficial effects of dietary resveratrol may derive in part by preventing mitochondrial ATP synthesis in tumor cells, thereby inducing apoptosis. mitochondria | oxidative phosphorylation | rotary mechanism | crystal structure