The structure of the Dead ringer–DNA complex reveals how AT‐rich interaction domains (ARIDs) recognize DNA

The AT‐rich interaction domain (ARID) is a DNA‐binding module found in many eukaryotic transcription factors. Using NMR spectroscopy, we have determined the first ever three‐dimensional structure of an ARID–DNA complex (mol. wt 25.7 kDa) formed by Dead ringer from Drosophila melanogaster . ARIDs recognize DNA through a novel mechanism involving major groove immobilization of a large loop that connects the helices of a non‐canonical helix–turn–helix motif, and through a concomitant structural rearrangement that produces stabilizing contacts from a β‐hairpin. Dead ringer's preference for AT‐rich DNA originates from three positions within the ARID fold that form energetically significant contacts to an adenine–thymine base step. Amino acids that dictate binding specificity are not highly conserved, suggesting that ARIDs will bind to a range of nucleotide sequences. Extended ARIDs, found in several sequence‐specific transcription factors, are distinguished by the presence of a C‐terminal helix that may increase their intrinsic affinity for DNA. The prevalence of serine amino acids at all specificity determining positions suggests that ARIDs within SWI/SNF‐related complexes will interact with DNA non‐sequence specifically.