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Trifluoperazine-induced conformational change in Ca2+-calmodulin

Nature Structural Biologyvolume 1pages795801 (1994) | Download Citation

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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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Affiliations

  1. Department of Biochemistry, University of Saskatchewan, Saskatoon, SK, Canada, S7N 0W0

    • Margaret Vandonselaar
    •  & Louis T. J. Delbaere
  2. Department of Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada, S7N 0W0

    • Robert A. Hickie
  3. Department of Chemistry, University of Saskatchewan, Saskatoon, SK, Canada, S7N 0W0

    • Wilson Quail

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https://doi.org/10.1038/nsb1194-795

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