Calmodulin is a member of a class of structurally and functionally related proteins. Calmodulin is widely distributed among eukaryotes, and the amino acid sequence of calmodulin is highly conserved. The protein contains multiple structural domains and has multiple activities in vitro, including calcium dependent drug binding. In the studies presented in this thesis, we have used phenothiazines as tools to probe the relationships between structural domains and functional domains in calmodulin. The approach to the problem of structure-function relationships can be framed in three questions: Do other calciurn modulated proteins show calcium dependent drug binding activity? What are the structural requirements for drug binding in calmodulin? How is the drug binding activity of calmodulin related to its enzyme activator and protein binding activities? In these questions lies the essence of our approach to the molecular aspects of the relationship between the inhibitory drug binding activities and the functional activities of calmodulin. While other investigators have studied the inhibitory actions of many classes of drugs on calmodulin, we have examined the properties of the protein and structurally related proteins in order to relate structure and function.

A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy