Here we show that, as a consequence of binding the drug trifluoperazin
e, a major conformational movement occurs in Ca2+-calmodulin (CaM). Th
e 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 Ca
2+-CaM by trifluoperazine is due to this major tertiary-structural alt
eration in Ca2+-CaM, which is initiated and stabilized by drug binding
. This conformational change is similar to that which occurs on the bi
nding 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 t
arget enzymes.