Defining and Exploiting Hypersensitivity Hotspots to Facilitate Abscisic Acid Agonist Optimization
| Autor: | Amita Kaundal, Sang-Youl Park, Erin L. Sternburg, Dezi Elzinga, Aditya S. Vaidya, Sean R. Cutler, Michael Bartsch, Mathilde Lachia, Assaf Mosquna, Sebastian Wendeborn, Fedor V. Karginov, Davide Sabbadin |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Agonist medicine.drug_class Mutant Arabidopsis Molecular Dynamics Simulation Quinolones Ligands 01 natural sciences Biochemistry 03 medical and health sciences chemistry.chemical_compound Gene Expression Regulation Plant medicine Receptor Abscisic acid Pyrabactin Regulation of gene expression Sulfonamides Pyr1 010405 organic chemistry Chemistry Arabidopsis Proteins fungi food and beverages Membrane Transport Proteins General Medicine Ligand (biochemistry) Plants Genetically Modified 0104 chemical sciences 030104 developmental biology Biophysics Molecular Medicine |
| Zdroj: | ACS chemical biology. 14(3) |
| ISSN: | 1554-8937 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|