Going green: phytohormone mimetics for drought rescue.

Plants must respond to environmental changes in order to thrive. Upon sensing drought, plants protect themselves from water loss by a cascade of events, including rapid closure of stomata on their leaf surfaces and gene expression (Cutler et al., 2010). Drought severity and duration may increase due to climate change, potentially triggering significant agricultural and economic losses in croplands worldwide. A better understanding of natural drought responses in plants may help scientists mitigate these impacts. Molecular and cellular systems in plants sense drought and activate signaling networks to enhance drought tolerance. The phytohormone responsible for activating drought resistance responses is abscisic acid (ABA), a fish-shaped small molecule with a hexagonal head group and an acidic tail (Fig. 1A). Early genetic screens of ABA-insensitive mutant plants identified protein phosphatases and transcription factors, indicating that drought signaling is controlled at many levels. The isolation of the chemical compound ABA from plants was first reported in the 1960s (Eagles and Wareing, 1963; Ohkuma et al., 1963), yet the identity of its natural receptor remained a mystery for almost half a century. Two research teams solved this mystery, yielding a breakthrough in understanding the ABA signal transduction pathway (Ma et al., 2009; Park et al., 2009). In one approach, Sean Cutler’s laboratory screened a chemical library to identify small molecules that mimicked ABA responses and identified pyrabactin, with pyridine and naphthalene rings linked by sulfonamide (Fig. 1B). Along with studies using yeast two-hybrid and mass spectrometry analyses of protein complexes (Ma et al., 2009; Santiago et al., 2009b; Nishimura et al., 2010), this research (Park et al., 2009) led to the discovery of the PYR/PYL/RCAR (for pyrabactin resistance1/PYR1like/regulatory component of ABA receptor) family of ABA receptor proteins. This family is well conserved in plants and has at least 13 members in Arabidopsis (Arabidopsis thaliana); their sequences and threedimensional crystallographic structures indicate that the amino acids forming the internal ABA-binding site are highly conserved (for PYR1, see Nishimura et al. [2009] and Santiago et al. [2009a]; coordinates of PYL1, PYL2, PYL3, PYL5, PYL9, and PYL10 have been made available by contributions of many laboratories [for review, see Cutler et al., 2010]). The synthetic pyrabactin, unlike the natural hormone, is selective for certain receptor family members, particularly those prevalent in seeds (Park et al., 2009). Indeed, pyrabactin is an activator (agonist) for PYR1 and PYL1 but an inhibitor (antagonist) for their close cousin PYL2 (Melcher et al., 2010). The chemical library screening approach has again proven powerful by yielding more discoveries in ABA signaling. By applying this technique, Cutler’s group and another group led by J.-K. Zhu, H.E. Xu, and Y. Xu identified novel ABA mimetics, including a less selective and more potent compound named quinabactin (Okamoto et al., 2013) or ABA mimic1 (Cao et al., 2013). Quinabactin shares the architecture of pyrabactin: two aromatic ring systems linked by sulfonamide (Fig. 1C). Both pyrabactin and quinabactin compounds are agonists for PYR1 and PYL1 in seeds, but quinabactin is more potent (Okamoto et al., 2013). Quinabactin, like ABA, effectively activates dimeric ABA receptors to inhibit Protein Phosphatase2C (PP2C) phosphatases, including HAB1 (Homology to Abscisic Acid-Insensitive1). Crystal structures of quinabactin-bound PYL2 in complex with the phosphatase HAB1 show that the ketone and sulfonamide moieties of quinabactin are keys for the decoy (Cao et al., 2013; Okamoto et al., 2013; Fig. 1C). Quinabactin also activates other pyrabactin-insensitive ABA receptors, thus reducing water loss in leaves and providing drought tolerance to growing plants (Cao et al., 2013; Okamoto et al., 2013). The identification of synthetic chemical compounds that mimic the effects of natural phytohormones offers both wonderful promise and significant challenges, as we have learned from similar rewards and Figure 1. Natural and artificial chemical compounds interacting with