NMR solution structure of the bicoid homeodomain bound to DNA and molecular dynamics simulations of the homeodomain/DNA complex

The homeodomain is a common DNA recognition motif consisting of three helices and an N-terminal arm that serves as a valuable model for exploring the basis of specific DNA recognition by proteins. Recognition of specific DNA sites, loosely defined by a TAAT core, is dependent on the side-chains of key amino acids in the N-terminal arm and the third "recognition" helix of the homeodomain. While much is known about homeodomain/DNA recognition, key questions concerning the role of individual amino acids and the extent of side-chain, DNA, and water dynamics during recognition remain, often focusing on the dynamic role of position 50 during recognition of the two bases immediately 3' to the 5'-TAAT-3'/3'-ATTA-5' core (ATTANN). The Bicoid homeodomain provides an interesting model system for addressing these and other questions, serving as the only known homeodomain that has a dual role in both transcriptional (DNA-binding) and translational (RNA-binding) control, discriminating between these two functions by a single amino acid, arginine 54. To add to the understanding of both general protein/DNA recognition and to the specific function of the Bicoid transcription factor homeodomain, we have determined the solution structure of the Bicoid homeodomain bound to the consensus duplex B-DNA binding site 5'-TAATCC-3'/3'-ATTAGG-5'. Our structure indicates that the Bicoid homeodomain exhibits variation from other homeodomain structures at the end of helix I, and NMR resonance line broadening of the K50 and R54 side-chains, consistent with side-chain motion and supportive of the adaptive-recognition theory of protein/DNA interactions.