Crystal structure of the complex of DUSP15 and its inhibitor reveals novel inhibitor binding interactions

Protein tyrosine phosphatases (PTPs) dephosphorylate their target proteins in various cell signaling processes and their dephosphorylation activities are associated with cancers, neurological disorders, and diabetes. Although PTPs are considered as promising drug targets, no PTP-targeting drugs are currently on the market. To understand inhibitor binding to PTP proteins, we determined crystal structure of the complex between DUSP15, a member of PTP family and its inhibitor. In the complex structure, extra electron density observed near the active site pocket was fitted to the inhibitor structure. The inhibitor binding site does not overlap the phosphate-binding active site. The novel inhibitor binding interactions involving the P-, D-, and β3-β4 loops indicate an allosteric inhibition mechanism of the inhibitor.