Crystal Structures of Engrailed Homeodomain Mutants: Implications for stability and dynamics

Elliott J. Stollar, Ugo Mayor, Simon C. Lovell, Luca Federici, Stefan M V Freund, Alan R. Fersht, Ben F. Luisi

    Research output: Contribution to journalArticlepeer-review


    We report the crystal structures and biophysical characterization of two stabilized mutants of the Drosophila Engrailed homeodomain that have been engineered to minimize electrostatic repulsion. Four independent copies of each mutant occupy the crystal lattice, and comparison of these structures illustrates variation that can be partly ascribed to networks of correlated conformational adjustments. Central to one network is leucine 26 (Leu 26), which occupies alternatively two side chain rotameric conformations (-gauche and trans) and different positions within the hydrophobic core. Similar sets of conformational substates are observed in other Engrailed structures and in another homeodomain. The pattern of structural adjustments can account for NMR relaxation data and sequence co-variation networks in the wider homeodomain family. It may also explain the dysfunction associated with a P26L mutation in the human ARX homeodomain protein. Finally, we observe a novel dipolar interaction between a conserved tryptophan and a water molecule positioned along the normal to the indole ring. This interaction may explain the distinctive fluorescent properties of the homeodomain family.
    Original languageEnglish
    Pages (from-to)43699-43708
    Number of pages9
    JournalJournal of Biological Chemistry
    Issue number44
    Publication statusPublished - 31 Oct 2003


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