T cells are the central mediators of the immune response. Agents that inhibit T cell proliferation, such as the immunosuppressive drugs cyclosporin A (CsA) and FK506, have revolutionized clinical organ transplantation. Despite their immense impact, these agents posses toxic side-effects that severely limit their long-term use in man patients. To address this problem, we have pursued a program that aims to discover new T cell-specific targets in the signaling pathway inhibited by FK506 and CsA. Through these efforts, we have isolated, cloned and overproduced a transcription factor termed the nuclear factor of activated T cells (NF- AT), which regulates cytokine gene induction in response to antigenic stimulation of T cells. NF-AT binds cooperatively to many of its regulatory sites together with a heterologous transcription factor, AP-1. For example, NF-AT and AP-1 bind cooperatively ot the ARRE2 site of the interleukin-2 (IL-2) enhancer, and this interaction is a key process in the initiation of T cell proliferation. Here we propose a series of multidimensional NMR experiments aimed at elucidating the structure of the NF-AT DNA-binding domain, and the structural basis for its specific interactions with ARRE2 and DNA. The results of these studies should serve as the basis for future efforts aimed at development of NF-AT antagonists.
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