Two distinct Cu–O–Cu2+ sites with methane monooxygenase activity are identified in the zeolite Cu-MOR, emphasizing that this Cu–O–Cu active site geometry, having a ∠Cu–O–Cu ∼140°, is particularly formed and stabilized in zeolite topologies. Whereas in ZSM-5 a similar Cu–O–Cu2+ active site is located in the intersection of the two 10 membered rings, Cu-MOR provides two distinct local structures, situated in the 8 membered ring windows of the side pockets. Despite their structural similarity, as ascertained by electronic absorption and resonance Raman spectroscopy, the two Cu–O–Cu active sites in Cu-MOR clearly show different kinetic behaviors in selective methane oxidation. This difference in reactivity is too large to be ascribed to subtle differences in the ground states of the Cu–O–Cu sites, indicating the zeolite lattice tunes their reactivity through second-sphere effects. The MOR lattice is therefore functionally analogous to the active site pocket of a metalloenzyme, demonstrating that both the active site and its framework environment contribute to and direct reactivity in transition metal ion-zeolites.