Allosteric Inhibition of PTP1B by a Nonpolar Terpenoid

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 allosteric
inhibition of PTP1B by amorphadiene (AD), a terpenoid hydrocarbon
that is an unusually selective inhibitor. Molecular dynamics (MD)
simulations carried out in this study suggest that AD can stably sample
multiple neighboring sites on the allosterically influential C-terminus
of the catalytic domain. Binding to these sites requires a disordered
α7 helix, which stabilizes the PTP1B–AD complex and may
contribute to the selectivity of AD for PTP1B over TCPTP. Intriguingly,
the binding mode of AD differs from that of the most well-studied
allosteric inhibitor of PTP1B. Indeed, biophysical measurements and
MD simulations indicate that the two molecules can bind simultaneously.
Upon binding, both inhibitors destabilize the α7 helix by disrupting
interactions at the α3−α7 interface and prevent
the formation of hydrogen bonds that facilitate closure of the catalytically
essential WPD loop. These findings indicate 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.