Abscisic Acid Signaling and Biosynthesis: Protein Structures and Molecular Probes

Helander, Jonathan D. M.; Cutler, Sean R.

doi:10.1007/978-3-319-91352-0_8

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“…PYR1 belongs to subfamily III, whose receptors possess, in general, lower ABA binding affinity than subfamily I and II receptors . Two of the hypersensitive residues defined by our screen (I110 and A160) differ in sequence between receptor subtypes (Figure S3), and prior work has demonstrated that sequence differences at these sites contribute to differences in both ABA sensitivity and agonist selectivity between receptor subtypes. − The other two hypersensitivity sites that we defined (V81 and E141) are invariant across receptor subtypes (Figure S3) and would not be predicted to alter sensitivity based on evolutionary considerations alone. Saturation mutagenesis can therefore be useful for defining hotspot residues that do not naturally contribute to differences in agonist sensitivity between receptor subtypes and/or that are highly conserved.…”

Section: Resultsmentioning

confidence: 84%

Defining and Exploiting Hypersensitivity Hotspots to Facilitate Abscisic Acid Agonist Optimization

et al. 2019

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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.

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