Drug interaction with calmodulin: the binding site

Abstract

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.