Allosteric Inhibition of PTP1B by a Nonpolar Terpenoid
The Journal of Physical Chemistry B(2022)
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.
### Competing Interest Statement
J.M.F. is a founder of Think Bioscience, Inc., which develops small-molecule therapeutics and employs J.M.F., A.S., and L.K. M.R.S. is an Open Science Fellow at and consultant for Roivant Sciences.
MoreTranslated text
AI Read Science
Must-Reading Tree
Example
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
Generate MRT to find the research sequence of this paper
Chat Paper
Summary is being generated by the instructions you defined