Structure-Based Chemical Design of Abscisic Acid Antagonists That Block PYL-PP2C Receptor Interactions

Jun Takeuchi, Naoki Mimura, Masanori Okamoto, Shunsuke Yajima, Masayuki Sue, Tomonori Akiyama, Keina Monda, Koh Iba, Toshiyuki Ohnishi, Yasushi Todoroki

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11 Citations (Scopus)

Abstract

In 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.

Original languageEnglish
Pages (from-to)1313-1321
Number of pages9
JournalACS Chemical Biology
Volume13
Issue number5
DOIs
Publication statusPublished - May 18 2018

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine

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    Takeuchi, J., Mimura, N., Okamoto, M., Yajima, S., Sue, M., Akiyama, T., Monda, K., Iba, K., Ohnishi, T., & Todoroki, Y. (2018). Structure-Based Chemical Design of Abscisic Acid Antagonists That Block PYL-PP2C Receptor Interactions. ACS Chemical Biology, 13(5), 1313-1321. https://doi.org/10.1021/acschembio.8b00105