RT Journal Article
SR Electronic
T1 Allosteric Inhibition of PTP1B by a Nonpolar Terpenoid
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.05.18.492571
DO 10.1101/2022.05.18.492571
A1 Anika J. Friedman
A1 Evan T. Liechty
A1 Levi Kramer
A1 Ankur Sarkar
A1 Jerome M. Fox
A1 Michael R. Shirts
YR 2022
UL http://biorxiv.org/content/early/2022/05/19/2022.05.18.492571.abstract
AB 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 α7 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 StatementJ.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.PTP1Bprotein tyrosine phosphatase 1BTCPTPT-cell protein tyrosine phosphataseMDmolecular dynamicsADamorphadieneBBR3-(3,5-Dibromo-4-hydroxy-benzoyl)-2-ethyl-benzofuran-6-sulfonicacid-(4-(thiazol-2-ylsulfamyl)-phenyl)-amideTCS4012-[(Carboxycarbonyl)amino]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid hydrochlo-rideDSSPDefined Secondary Structure Prediction