Influence of Ca2+ and Trifluoperazine on the Structure of Calmodulin

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Abstract
Ca2+-induced conformational changes of calmodulin under a variety of different experimental conditions were studied by 1H-NMR techniques. The assignment for Tyr-99 was corrected. Ca2+ titration performed at pH 7.5 and > 9.5 apparently induces a different sequence of the protein folding process as can be monitored by the resonances of His-107. These 2 structural forms cannot be interconverted. The phenylalanine residue(s) responsible for the resonances at 6.47 ppm (Ca2+-free form) and 6.64 ppm (Ca2+-saturated form), respectively, are apparently located close to Ca2+-binding sites III and IV. This can be recognized from nuclear Overhauser enhancement and Gd3+-broadening techniques. Gd3+-broadening experiments classify Ca2+-binding site IV as the site with the highest Gd3+/Ca2+-exchange rate. The antipsychotic drug trifluoperazine, which is known to bind to calmodulin in a Ca-dependent way induced a conformational change of the Ca2+-saturated form of calmodulin. The methionine and phenylalanine residues were especially affected. Possible binding site(s) for trifluoperazine are discussed.