Drug interaction with calmodulin: the binding site.

Demonstration of major tranquillizer binding to bovine brain calmodulin and a fragment of the natural protein as well as a synthetic analog of a single calcium binding site in calmodulin has led to the hypothesis that the drug binding site is located in one or both of two possible linear amino acid sequences in the natural protein. The sequences are approximately ten residues in length and both consist of a calcium sensitive alpha-helical segment of the protein which is characterized by a hydrophobic region and an acidic hydrophilic region separated by one half turn of the alpha-helix. The protein hydrophobic region contains two aromatic phenylalanine residues which are oriented by the alpha-helix in such a way as to overlap the II orbitals of the aromatic groups in the major tranquillizers thus explaining the preference of the binding site for phenothiazine like structures. The hydrophilic region of the protein's drug binding site consists of two and possibly three acid residues which are postulated to interact with the basic center in the side chain of the major tranquillizers.

[1]  J. Head,et al.  Identification and purification of a phenothiazine binding fragment from bovine brain calmodulin , 1982, FEBS letters.

[2]  T. Tanaka,et al.  Hydrophobic regions function in calmodulin-enzyme(s) interactions. , 1980, The Journal of biological chemistry.

[3]  A. H. Drummond,et al.  Inhibition of calcium-dependent regulator-stimulated phosphodiesterase activity by neuroleptic drugs is unrelated to their clinical efficacy. , 1979, Molecular pharmacology.

[4]  R. Hodges,et al.  Calcium-induced protein folding. Structure-affinity relationships in synthetic analogs of the helix-loop-helix calcium binding unit. , 1981, The Journal of biological chemistry.

[5]  S. Perry.  The regulation of contractile activity in muscle. , 1979, Biochemical Society transactions.

[6]  B. Weiss,et al.  Specificity of the binding of trifluoperazine to the calcium-dependent activator of phosphodiesterase and to a series of other calcium-binding proteins. , 1978, Biochimica et biophysica acta.

[7]  B. Weiss,et al.  Mechanism by which psychotropic drugs inhibit adenosine cyclic 3',5'-monophosphate phosphodiesterase of brain. , 1976, Molecular pharmacology.

[8]  S. Snyder,et al.  Properties of [3H]haloperidol and [3H]dopamine binding associated with dopamine receptors in calf brain membranes. , 1976, Molecular pharmacology.

[9]  B. Weiss,et al.  Interaction of drugs with calmodulin. Biochemical, pharmacological and clinical implications. , 1982, Biochemical pharmacology.

[10]  F. Vincenzi,et al.  Calmodulin activation of red blood cell (Ca2+ + Mg2+)-ATPase and its antagonism by phenothiazines. , 1980, Molecular pharmacology.

[11]  S. Perry,et al.  Biological activities of the peptides obtained by digestion of troponin C and calmodulin with thrombin. , 1981, The Biochemical journal.

[12]  R. Hodges,et al.  Co-operativity and calcium/magnesium binding to troponin C and muscle calcium binding parvalbumin: an hypothesis. , 1980, Journal of theoretical biology.

[13]  P. Greengard,et al.  Dopamine-Sensitive Adenyl Cyclase: Possible Role in Synaptic Transmission , 1971, Science.

[14]  B. Roufogalis,et al.  Phenothiazine antagonism of calmodulin: a structurally-nonspecific interaction. , 1981, Biochemical and biophysical research communications.

[15]  D. Storm,et al.  Calcium-induced exposure of a hydrophobic surface on calmodulin. , 1980, Biochemistry.

[16]  S. Rosenfeld,et al.  Proteolytic fragments of troponin C. Interactions with the other troponin subunits and biological activity. , 1981, The Journal of biological chemistry.