Dual-specificity protein phosphatases (DUSPs), which dephosphorylate both 
phosphoserine/threonine and phosphotyrosine, play vital roles in immune 
activation, brain function and cell-growth signalling. A family-wide structural 
library of human DUSPs was constructed based on experimental structure 
determination supplemented with homology modelling. The catalytic domain of each 
individual DUSP has characteristic features in the active site and in 
surface-charge distribution, indicating substrate-interaction specificity. The 
active-site loop-to-strand switch occurs in a subtype-specific manner, 
indicating that the switch process is necessary for characteristic substrate 
interactions in the corresponding DUSPs. A comprehensive analysis of the 
activity-inhibition profile and active-site geometry of DUSPs revealed a novel 
role of the active-pocket structure in the substrate specificity of DUSPs. A 
structure-based analysis of redox responses indicated that the additional 
cysteine residues are important for the protection of enzyme activity. The 
family-wide structures of DUSPs form a basis for the understanding of 
phosphorylation-mediated signal transduction and the development of 
therapeutics.