Comparative Biochemistry of Drug-Binding Proteins in Calmodulin/S100 Family

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 (134- 137) 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

Toll-like receptors and innate immune responses in systemic lupus erythematosus

A series of discoveries over the past several years has provided a new paradigm for understanding autoimmunity in systemic lupus erythematosus. The discoveries of pattern recognition receptors and of how these receptors can be recruited into autoimmune responses underpin this paradigm. The implications of these observations continue to unfold with ongoing investigation into the range and specificity of pattern recognition receptors, into how immune complexes containing nucleic acids trigger these receptors, into how endogenous macromolecular 'danger signals' stimulate innate immune responses, and into the effect of pattern recognition receptor activation on various cell types in initiating and perpetuating autoimmunity. The development of clinical trials using therapeutic agents that target components of the innate immune system suggests that these advances may soon culminate in new medications for treating patients with systemic lupus erythematosus