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Related flavonoids cause cooperative inhibition of the sarcoplasmic reticulum Ca²⁺ ATPase by multimode mechanisms.Flavonoids are group of plant-derived hydroxylated polycyclic molecules found in fruit and vegetables. They are known to bio-accumulate within humans and are considered to have beneficial health effects, including cancer chemoprotection. One mechanism proposed to explain this is that they are able to induce apoptosis in cancer cells by inhibiting a variety of kinases and also the Ca²⁺ ATPase. An investigation was undertaken with respect to the mechanism of inhibition for three flavonoids: quercetin, galangin and 3,6 dihydroxyflavone (3,6-DHF). Each inhibited the Ca²⁺ ATPase with K(i) values of 8.7, 10.3 and 5.4 μM, respectively, showing cooperative inhibition with n ~ 2. Given their similar structures, the flavonoids showed several differences in their mechanisms of inhibition. All three flavonoids stabilized the ATPase in the E₁ conformation and reduced [³²P]-ATP binding. However, both galangin and 3,6-DHF increased the affinity of Ca²⁺ for the ATPase by decreasing the Ca²⁺-dissociation rate constant, whereas quercetin had little effect. Ca²⁺-induced changes in tryptophan fluorescence levels were reduced in the presence of 3,6-DHF and galangin (but not with quercetin), indicating that Ca²⁺-associated changes within the transmembrane helices are altered. Both galangin and quercetin reduced the rates of ATP-dependent phosphorylation and dephosphorylation, whereas 3,6-DHF did not. Modelling studies suggest that flavonoids could potentially bind to two sites: one directly where nucleotides bind within ATP binding site and the other at a site close by. We hypothesize that interactions of these two neighbouring sites may account for both the cooperative inhibition and the multimode mechanisms of action seen with related flavonoids.