Nature Structural Biology
1, 795 - 801 (1994)
doi:10.1038/nsb1194-795
Trifluoperazine-induced conformational change in Ca2+-calmodulinMargaret Vandonselaar1, Robert A. Hickie2, Wilson Quail3
& Louis T. J. Delbaere1
1Department of Biochemistry, University of Saskatchewan, Saskatoon, SK, Canada S7N 0W0
2Department of Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada S7N 0W0
3Department of Chemistry, University of Saskatchewan, Saskatoon, SK, Canada S7N 0W0 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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