Trifluoperazine-induced conformational change in Ca(2+)-calmodulin.
Here we show that, as a consequence of binding the drug trifluoperazine, a major conformational movement occurs in Ca(2+)-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 Ca(2+)-CaM by trifluoperazine is due to this major tertiary-structural alteration in Ca(2+)-CaM, which is initiated and stabilized by drug binding. This conformational change is similar to that which occurs on the binding of Ca(2+)-CaM to target peptides. Two hydrophobic binding pockets, created by amino acid residues adjacent to Ca(2+)-coordinating residues, form the key recognition sites on Ca(2+)-CaM for both inhibitors and target enzymes.
Vandonselaar
M
M
Department of Biochemistry, University of Saskatchewan, Saskatoon, Canada.
Hickie
R A
RA
Quail
J W
JW
Delbaere
L T
LT
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000737:chemistry*; D002147:Calmodulin / Q000737:chemistry* / Q000378:metabolism; D002417:Cattle; D018360:Crystallography, X-Ray; D008969:Molecular Sequence Data; D011487:Protein Conformation; D014268:Trifluoperazine / Q000737:chemistry* / Q000378:metabolism
D002147:Calmodulin; D014268:Trifluoperazine; D002118:Calcium