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.
Two trifluoperazine-binding sites on calmodulin predicted from comparative molecular modeling with troponin-C.,Strynadka NC, James MN Proteins. 1988;3(1):1-17. PMID:3375233[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
↑ Strynadka NC, James MN. Two trifluoperazine-binding sites on calmodulin predicted from comparative molecular modeling with troponin-C. Proteins. 1988;3(1):1-17. PMID:3375233 doi:http://dx.doi.org/10.1002/prot.340030102
