text: The EFI is developing an integrated sequence-structure based strategy for functional assignment by predicting the substrate specificities of unknown members of mechanistically diverse enzyme superfamilies.  The approach leverages conserved features within a given superfamily such as known chemistry, identity of active site functional groups, and composition of specificity-determining residues, motifs, or structures to predict function but relies on multidisciplinary expertise to streamline, refine, and test the predictions.  The integrated sequence-strategy under development will be generally applicable to deciphering the ligand specificities of any functionally unknown protein.