Allosteric regulation is exploited by biological systems to regulate the activity and/or selectivity of enzymatic reactions but remains a challenge for artificial catalysts. Here we report switchable terpy(Zn-salphen) 2 molecular tweezers and their metal-dependent allos-teric regulation of the acetylation of pyridinemethanol isomers. Zinc-salphen moieties can both act as a Lewis acid to activate the anhydride reagents and provide a binding site for pyridinemethanol substrates. The tweezers' conformation can be reversibly switched between an open and a closed form by a metal ion stimulus. Both states offer distinct catalytic profiles, with closed tweezers showing superior catalytic activity towards ortho substrates, while open tweezers presenting higher rate for the acetylation of meta and para substrates. This notable substrate dependent allosteric response is rationalized by a combination of experimental results and calculations supporting a bimetallic reaction in the closed form for ortho substrate and an inhibition of the cavity for meta and para substrates.