Structural basis of sialyltransferase activity in trypanosomal sialidases

The intracellular parasite Trypanosoma cruzi, the etiological agent of Chag as disease, sheds a developmentally regulated surface trans-sialidase, whic h is involved in key aspects of parasite-host cell interactions. Although i t shares a common active site architecture with bacterial neuraminidases, t he T.cruzi enzyme behaves as a highly efficient sialyltransferase. Here we report the crystal structure of the closely related Trypanosoma rangeli sia lidase and its complex with inhibitor. The enzyme folds into two distinct d omains: a catalytic beta-propeller fold tightly associated with a lectin-li ke domain. Comparison with the modeled structure of T.cruzi trans-sialidase and mutagenesis experiments allowed the identification of amino acid subst itutions within the active site cleft that modulate sialyltransferase activ ity and suggest the presence of a distinct binding site for the acceptor ca rbohydrate, The structures of the Trypanosoma enzymes illustrate how a glyc osidase scaffold can achieve efficient glycosyltransferase activity and pro vide a framework for structure-based drug design.