The homeobox domain or homeodomain was first identified in a number of drosophila homeotic and segmentation proteins, but is now known to be well-conserved in many other animals, including vertebrates [1, 2, 3]. Hox genes encode homeodomain-containing transcriptional regulators that operate differential genetic programs along the anterior-posterior axis of animal bodies [4]. The domain binds DNA through a helix-turn-helix (HTH) structure. The HTH motif is characterised by two alpha-helices, which make intimate contacts with the DNA and are joined by a short turn. The second helix binds to DNA via a number of hydrogen bonds and hydrophobic interactions, which occur between specific side chains and the exposed bases and thymine methyl groups within the major groove of the DNA [5]. The first helix helps to stabilise the structure.

The motif is very similar in sequence and structure in a wide range of DNA-binding proteins (e.g., cro and repressor proteins, homeotic proteins, etc.). One of the principal differences between HTH motifs in these different proteins arises from the stereo-chemical requirement for glycine in the turn which is needed to avoid steric interference of the beta-carbon with the main chain: for cro and repressor proteins the glycine appears to be mandatory, while for many of the homeotic and other DNA-binding proteins the requirement is relaxed.

1. The structure and function of the homeodomain. Biochim. Biophys. Acta 989, 25-48
2. The homeobox in perspective. Trends Biochem. Sci. 17, 277-80
3. Patterns, puzzles and paradigms - The riddle of the homeobox. Trends Neurosci. 10, 3-6
4. Hox proteins: sculpting body parts by activating localized cell death. Curr. Biol. 12, R776-8

The homeobox domain or homeodomain was first identified in a number of drosophila homeotic and se
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