Abstract: The present invention provides compositions and methods for investigating the structural basis of the activation process of CRAC channels, which are essential for T-lymphocyte activation and adaptive immunity. The invention also provides compositions and methods to design, identify and evaluate agents that modulate calcium signaling by regulating the interaction between STIM and Orai proteins. The invention also provides therapeutic agents for cases of immunological disorders, compromised immune function, organ transplantation, or thrombosis.