interface at the C-lobe. This is consistent with mutagenesis data from other groups on the full length GNE protein [11, 18] . The crystallographic hexamer, which consists of a trimer of kinase dimers, could serve as a prototype of a proposed full length GNE hexamer. Structure comparison of the GNE kinase domain with previously studied proteins revealed potential substrate binding sites at the interlobar cleft and also the structural and functional importance of the signature zinc-binding motif of the ROK family. Four groups of missense mutations associated with hereditary inclusion body myopathy are classified and their effects on the enzymatic activity can mostly be explained by the structure model.