Allosteric Inhibition of PTP1B by a Nonpolar Terpenoid

Abstract

Protein tyrosine phosphatases (PTPs) are promising drug targets for treating a wide range of diseases such as diabetes, cancer, and neurological disorders, but their conserved active sites have complicated the design of selective therapeutics. This study examines the inhibition of PTP1B by amorphadiene (AD), an unusually selective terpenoid inhibitor. Molecular dynamics (MD) simulations in this study suggest that AD can sample two neighboring sites on the allosterically influential C-terminus of the catalytic domain. Binding to these sites requires a disordered $\alpha$7 helix, which stabilizes the PTP1B-AD complex and may contribute to the selectivity of AD for PTP1B over TCPTP, its closest homologue. The binding mode of AD differs from that of a previously reported allosteric inhibitor; notably, biophysical measurements and MD simulations indicate that the two molecules can bind simultaneously. Upon binding, both inhibitors destabilize the α7 helix and disrupt hydrogen bonds that facilitate closure of the catalytically essential WPD loop. These findings suggest that AD is a promising scaffold for building allosteric inhibitors of PTP1B and illustrate, more broadly, how unfunctionalized terpenoids can engage in specific interactions with protein surfaces.

Room-temperature serial synchrotron crystallography of apo PTP1B

“…Because active-site inhibitors of PTP1B suffer from bioavailability and selectivity limitations (Stanford and Bottini 2017), notwithstanding some progress in bypassing such limitations (Z. Y. Zhang 2001), there has been increasing focus on the potential of allosteric inhibition. Several allosteric inhibitors targeting different sites in PTP1B have been reported in the literature (Wiesmann et al 2004;Hansen et al 2005;Krishnan et al 2014Krishnan et al , 2018Keedy et al 2018;Friedman et al 2022). However, to date, none have been clinically approved, illustrating the persistent need to elucidate conformational ensembles and allosteric mechanisms in this protein.…”