Two trifluoperazine-binding sites on calmodulin predicted from comparative molecular modeling with troponin-C.
Among the known regulatory proteins that are conformationally sensitive to the binding of calcium ions, calmodulin and troponin-C have the greatest primary sequence homology. This observation has led to the conclusion that the most accurate predicted molecular model of calmodulin would be based on the X-ray crystallographic coordinates of the highly refined structure of turkey skeletal troponin-C. This paper describes the structure of calmodulin built from such a premise. The resulting molecular model was subjected to conjugate gradient energy minimization to remove unacceptable intramolecular non-bonded contacts. In the analysis of the resulting structure, many features of calmodulin, including the detailed conformation of the Ca2+-binding loops, the amino- and carboxy-terminal hydrophobic patches of the Ca2+-bound form, and the several clusters of acidic residues can be reconciled with much of the previously published solution data. Calmodulin is missing the N-terminal helix characteristic of troponin-C. The deletion of three residues from the central helical linker (denoted D/E in troponin-C) shortens the molecule and changes the orientation of the two domains of calmodulin by 60 degrees relative to those in troponin-C. The molecular model has been used to derive two possible binding sites for the antipsychotic drug trifluoperazine, a potent competitive inhibitor of calmodulin activity.
Strynadka
N C
NC
Medical Research Council of Canada Group in Protein Structure and Function, Department of Biochemistry, University of Alberta, Edmonton.
James
M N
MN
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism*; D002417:Cattle; D002645:Chickens; D003198:Computer Simulation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D011817:Rabbits; D013045:Species Specificity; D014268:Trifluoperazine / Q000378:metabolism*; D014336:Troponin / Q000378:metabolism*; D019209:Troponin C
D002135:Calcium-Binding Proteins; D002147:Calmodulin; D014336:Troponin; D019209:Troponin C; D014268:Trifluoperazine