Abietane-Type Diterpenoids Inhibit Protein Tyrosine Phosphatases by Stabilizing an Inactive Enzyme Conformation.

Biochemistry
Michael K HjortnessJerome M Fox

Abstract

Protein tyrosine phosphatases (PTPs) contribute to a striking variety of human diseases, yet they remain vexingly difficult to inhibit with uncharged, cell-permeable molecules; no inhibitors of PTPs have been approved for clinical use. This study uses a broad set of biophysical analyses to evaluate the use of abietane-type diterpenoids, a biologically active class of phytometabolites with largely nonpolar structures, for the development of pharmaceutically relevant PTP inhibitors. Results of nuclear magnetic resonance analyses, mutational studies, and molecular dynamics simulations indicate that abietic acid can inhibit protein tyrosine phosphatase 1B, a negative regulator of insulin signaling and an elusive drug target, by binding to its active site in a non-substrate-like manner that stabilizes the catalytically essential WPD loop in an inactive conformation; detailed kinetic studies, in turn, show that minor changes in the structures of abietane-type diterpenoids (e.g., the addition of hydrogens) can improve potency (i.e., lower IC50) by 7-fold. These findings elucidate a previously uncharacterized mechanism of diterpenoid-mediated inhibition and suggest, more broadly, that abietane-type diterpenoids are a promising source o...Continue Reading

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Citations

Nov 20, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Natalia A LuchnikovaIrina B Ivshina
Feb 9, 2020·Nature Communications·Akarawin HongdusitJerome M Fox
Jan 16, 2021·Biochemistry·Akarawin Hongdusit, Jerome M Fox
Feb 24, 2021·Journal of Molecular Recognition : JMR·Mingqiong TongYan Wang
May 15, 2021·ACS Synthetic Biology·Ankur SarkarJerome M Fox
Oct 6, 2018·Biochemistry·Michael K HjortnessJerome M Fox
Dec 14, 2021·ACS Synthetic Biology·Akarawin HongdusitJerome M Fox

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