Abstract
Here we show that, as a consequence of binding the drug trifluoperazine, a major conformational movement occurs in Ca2+-calmodulin (CaM). The tertiary structure changes from an elongated dumb-bell, with exposed hydrophobic surfaces, to a compact globular form which can no longer interact with its target enzymes. It is likely that inactivation of Ca2+-CaM by trifluoperazine is due to this major tertiary-structural alteration in Ca2+-CaM, which is initiated and stabilized by drug binding. This conformational change is similar to that which occurs on the binding of Ca2+-CaM to target peptides. Two hydrophobic binding pockets, created by amino acid residues adjacent to Ca2+-coordinating residues, form the key recognition sites on Ca2+-CaM for both inhibitors and target enzymes.
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Vandonselaar, M., Hickie, R., Quail, W. et al. Trifluoperazine-induced conformational change in Ca2+-calmodulin. Nat Struct Mol Biol 1, 795–801 (1994). https://doi.org/10.1038/nsb1194-795
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DOI: https://doi.org/10.1038/nsb1194-795
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