UNUSUAL REL-LIKE ARCHITECTURE IN THE DNA-BINDING DOMAIN OF THE TRANSCRIPTION FACTOR NFATC

TRANSCRIPTION factors of the NFAT family regulate the production of ef fector proteins that coordinate the immune response(1). The immunosupp ressive drugs FK506 and cyclosporin A (CsA) act by blocking a Ca2+-med iated signalling pathway leading to NFAT. Although FK506 and CsA have enabled human organs to Re transplanted routinely, the toxic side-effe cts of these drugs limit their usage. This toxicity might be absent in antagonists that target NFAT directly. As a first step in the structu re-based search for NFAT antagonists, we now report the identification and solution structure of a 20K domain of NFATc (NFATc-DBD) that is b oth necessary and sufficient to bind DNA and activate transcription co operatively. Although the overall fold of the NFATc DNA-hinding domain is related to that of NF-kappa B p50 (refs 2, 3), the two proteins us e significantly different strategies for DNA recognition. On the basis of these results, we present a model for the cooperative complex form ed between NFAT and the mitogenic transcription factor AP-1 on the int erleukin-2 enhancer.