Crystal structure determination and allosteric inhibition site prediction of DUSP13A

Abstract

DUSP13A also known as MDSP (muscle-restricted DUSP) is a member of the dual-specificity phosphatases (DUSPs) subgroup of protein tyrosine phosphatases (PTPs). DUSP13A is classified as an atypical DUSP which lacks the N-terminal CH2 domain and is located in human chromosome 10q22.2 with DUSP13B. DUSP13A is overexpressed at postnatal muscle development and reported to be the positive regulator of Apoptosis signal-regulating kinase 1 (ASK1), which is a MAP kinase kinase kinase, unlike other DUSPs which usually interacts MAPK (mitogen-activated protein kinase). Here, we determined the crystal structure of DUSP13A 5M (C18A, C35A, C77A, C129S, C176A, residues 13-185) at 1.69Å resolution using X-ray crystallography and found that DUSP13A has different structural features compared to other DUSPs sharing similar amino acid sequences, such as DUSP13B and VHR. PTP inhibitor V was developed for active site inhibition of SHP2. PTPs such as SHP2, DUSP13B and DUSP22 are inhibited by PTP inhibitor V on their active site. However, with DUSP13A, PTP Inhibitor V interacted with an allosteric site. It inhibits DUSP13A’s enzymatic reaction by blocking the product formation. We predicted the interaction site of PTP inhibitor V using docking simulation tools.