Summary

The crystal structure of the paired homeodomain bound to DNA as a cooperative dimer has been deter-mined to 2.0.a. resolution. Direct contacts between each homeodomain and the DNA are similar to those described previously. In addition, an extensive net-work of water molecules mediates contacts between the recognition helix and the DNA major groove. Sev-eral symmetrical contacts between the two homeodo-mains underlie the cooperative interaction, and defor-mations in the DNA structure are necessary for the establishment of these contacts. Comparison with structures of homeodomains bound monomerically to DNA suggests that the binding of a single paired ho-meodomain can introduce these DNA distortions, thus preparing a template for the cooperative interaction with a second homeodomain. This study shows how the paired (Pax) class homeodomains have achieved cooperativity in DNA binding without the assistance of other domains, thereby enabling the recognition of target sequences that are long enough to ensure speci-ficity