Identification of Allosteric Inhibitor Binding site of RPTPσ

Abstract

Protein tyrosine phosphatases (PTPs) are important regulators of protein tyrosine kinases (PTK) involved in various signaling pathways. PTP family is largely divided into the dual specificity phosphatases (DUSPs) and the classical PTPs. Since the PTPs are associated with various diseases, PTPs are considered as a promising drug target. However, development of competitive inhibitors targeting PTPs has several limitations, lack of selectivity and poor membrane permeability. Thus, allosteric inhibitors would be useful alternative to overcome these barriers. Among classical PTPs, RPTPσ is receptor like PTPs (RPTPs) that plays a central role in neural development, regarded as one of the drug targets. Despite identification of candidate compounds for allosteric inhibitors on RPTPσ, it was restricted to improve the inhibitors mainly due to unclear inhibitor binding site. Here, I identified allosteric inhibitor binding site of RPTPσ through mutagenesis and activity assay. RPTPσ E1562 was less inhibited compared to RPTPσ wild-type, as indicated by IC50 values. Also, it was revealed that the inhibitor has selectivity about classical PTPs through comparing classical PTPs and other subgroups of PTPs. Docking simulation showed detailed binding site and interactions of RPTPσ with the allosteric inhibitor.