Defining and Exploiting Hypersensitivity Hotspots to Facilitate Abscisic Acid Agonist Optimization

Dezi Elzinga, Erin Sternburg, Davide Sabbadin, Michael Bartsch, Sang Youl Park, Aditya Vaidya, Assaf Mosquna, Amita Kaundal, Sebastian Wendeborn, Mathilde Lachia*, Fedor V. Karginov, Sean R. Cutler

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Pyrabactin resistance 1 (PYR1) and related abscisic acid (ABA) receptors are new targets for manipulating plant drought tolerance. Here, we identify and use PYR1 hypersensitive mutants to define ligand binding hotspots and show that these can guide improvements in agonist potency. One hotspot residue defined, A160, is part of a pocket that is occupied by ABA's C6 methyl or by the toluyl methyl of the synthetic agonist quinabactin (QB). A series of QB analogues substituted at the toluyl position were synthesized and provide up to 10-fold gain in activity in vitro. Furthermore, we demonstrate that hypersensitive receptors can be used to improve the sensitivity of a previously described mammalian cell ABA-regulated transcriptional circuit by three orders of magnitude. Collectively, our data show that the systematic mapping of hypersensitivity sites in a ligand-binding pocket can help guide ligand optimization and tune the sensitivity of engineered receptors.

Original languageAmerican English
Pages (from-to)332-336
Number of pages5
JournalACS Chemical Biology
Volume14
Issue number3
DOIs
StatePublished - 15 Mar 2019

Bibliographical note

Publisher Copyright:
© 2019 American Chemical Society.

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