Structure of a HoxB1-Pbx1 heterodimer bound to DNA: Role of the hexapeptide and a fourth homeodomain helix in complex formation

Hox homeodomain proteins are developmental regulators that determine body p lan in a variety of organisms. A majority of the vertebrate Hox proteins bi nd DNA as heterodimers with the Pbx1 homeodomain protein. We report here th e 2.35 Angstrom structure of a ternary complex containing a human HoxB1-Pbx 1 heterodimer bound to DNA. Heterodimer contacts are mediated by the hexape ptide of HoxB1, which binds in a pocket in the Pbx1 protein formed in part by a three-amino acid insertion in the Pbx1 homeodomain. The Pbx1 DNA-bindi ng domain is larger than the canonical homeodomain, containing an additiona l alpha helix that appears to contribute to binding of the HoxB1 hexapeptid e and to stable binding of Pbx1 to DNA. The structure suggests a model for modulation of Hox DNA binding activity by Pbx1 and related proteins.