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Structure-Based Chemical Design of Abscisic Acid Antagonists That Block PYL–PP2C Receptor Interactions
journal contribution
posted on 2018-04-05, 00:00 authored by Jun Takeuchi, Naoki Mimura, Masanori Okamoto, Shunsuke Yajima, Masayuki Sue, Tomonori Akiyama, Keina Monda, Koh Iba, Toshiyuki Ohnishi, Yasushi TodorokiIn Arabidopsis, signaling of the stress hormone
abscisic acid (ABA) is mediated by PYR/PYL/RCAR receptors (PYLs),
which bind to and inhibit group-A protein phosphatases 2C (PP2Cs),
the negative regulators of ABA. X-ray structures of several PYL-ABA
and PYL-ABA-PP2C complexes have revealed that a conserved tryptophan
in PP2Cs is inserted into a small tunnel adjacent to the C4′
of ABA in the PYL-ABA complex and plays a crucial role in the formation
and stabilization of the PYL-ABA-PP2C complex. Here, 4′-modified
ABA analogues were designed to prevent the insertion of the tryptophan
into the tunnel adjacent to the C4′ of ABA in these complexes.
These analogues were predicted to block PYL–PP2C receptor interactions
and thus block ABA signaling. To test this, 4′-O-phenylpropynyl ABA analogues were synthesized as novel PYL antagonists
(PANs). Structural, thermodynamic, biochemical, and physiological
studies demonstrated that PANs completely abolished ABA-induced PYL–PP2C
interactions in vitro and suppressed stress-induced
ABA responses in vivo more strongly than did 3′-hexylsulfanyl-ABA
(AS6), a PYL antagonist we developed previously. The PANs and AS6
antagonized the effects of ABA to different degrees in different plants,
suggesting that these PANs can function as chemical scalpels to dissect
the complicated regulatory mechanism of ABA signaling in plants.