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Designed abscisic acid analogs as antagonists of PYL-PP2C receptor interactions

Nature Chemical Biology volume 10, pages 477482 (2014) | Download Citation

Abstract

The plant stress hormone abscisic acid (ABA) is critical for several abiotic stress responses. ABA signaling is normally repressed by group-A protein phosphatases 2C (PP2Cs), but stress-induced ABA binds Arabidopsis PYR/PYL/RCAR (PYL) receptors, which then bind and inhibit PP2Cs. X-ray structures of several receptor–ABA complexes revealed a tunnel above ABA's 3′ ring CH that opens at the PP2C binding interface. Here, ABA analogs with sufficiently long 3′ alkyl chains were predicted to traverse this tunnel and block PYL-PP2C interactions. To test this, a series of 3′-alkylsulfanyl ABAs were synthesized with different alkyl chain lengths. Physiological, biochemical and structural analyses revealed that a six-carbon alkyl substitution produced a potent ABA antagonist that was sufficiently active to block multiple stress-induced ABA responses in vivo. This study provides a new approach for the design of ABA analogs, and the results validated structure-based design for this target class.

  • Compound C15H20O4

    Abscisic acid

  • Compound C15H20O5

    2'α,3'α-Dihydro-2'α,3'α-epoxy-abscisic acid

  • Compound C17H24O4S

    AS2

  • Compound C18H26O4S

    AS3

  • Compound C19H28O4S

    AS4

  • Compound C20H30O4S

    AS5

  • Compound C21H32O4S

    AS6

  • Compound C22H34O4S

    AS7

  • Compound C23H36O4S

    AS8

  • Compound C24H38O4S

    AS9

  • Compound C25H40O4S

    AS10

  • Compound C26H42O4S

    AS11

  • Compound C27H44O4S

    AS12

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Acknowledgements

We thank T. Nakagawa for providing pGWB vectors and Toray Industries Inc., Tokyo, Japan, for the gift of (+)-ABA. This work was supported in part by the Japanese Society for the Promotion of Science (JSPS) Postdoctoral Fellowships for Research Abroad (to M.O.), JSPS KAKENHI (Grant-in-Aid for Young Scientists 26711018 to M.O.) and the US National Science Foundation (Integrative Organismal Systems 0820508 to S.R.C.).

Author information

Author notes

    • Akira Endo

    Present address: Crop Breeding Research Division, National Agricultural Research Organization for Hokkaido Region, Hokkaido, Japan.

    • Jun Takeuchi
    •  & Masanori Okamoto

    These authors contributed equally to this work.

Affiliations

  1. Graduate School of Science and Technology, Shizuoka University, Shizuoka, Japan.

    • Jun Takeuchi
    •  & Yasushi Todoroki
  2. Arid Land Research Center, Tottori University, Tottori, Japan.

    • Masanori Okamoto
  3. Department of Botany and Plant Sciences and Center for Plant Cell Biology, University of California–Riverside, Riverside, California, USA.

    • Masanori Okamoto
    •  & Sean R Cutler
  4. Department of Bioscience, Tokyo University of Agriculture, Tokyo, Japan.

    • Tomonori Akiyama
    •  & Shunsuke Yajima
  5. Graduate School of Agriculture, Shizuoka University, Shizuoka, Japan.

    • Takuya Muto
    • , Toshiyuki Ohnishi
    •  & Yasushi Todoroki
  6. Department of Applied Biology and Chemistry, Tokyo University of Agriculture, Tokyo, Japan.

    • Masayuki Sue
  7. RIKEN Center for Sustainable Resource Science, Kanagawa, Japan.

    • Mitsunori Seo
    •  & Yuri Kanno
  8. National Institute for Agro-Environmental Sciences, Ibaraki, Japan.

    • Tsunashi Kamo
  9. Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada.

    • Akira Endo
    •  & Eiji Nambara
  10. Graduate School of Agriculture, Kyoto University, Kyoto, Japan.

    • Nobuhiro Hirai
  11. Research Institute of Green Science and Technology, Shizuoka University, Shizuoka, Japan.

    • Toshiyuki Ohnishi
    •  & Yasushi Todoroki

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Contributions

J.T., M.O. and Y.T. conceived and J.T., M.O., S.R.C. and Y.T. designed the research. J.T., M.O., T.A., T.M., S.Y., M. Sue, M. Seo, Y.K., K.T., A.E., E.N., S.R.C. and Y.T. performed the research and/or analyzed data. J.T., M.O., S.R.C. and Y.T. co-wrote the manuscript with the assistance of M. Sue, M. Seo, N.H. and T.O.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Yasushi Todoroki.

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DOI

https://doi.org/10.1038/nchembio.1524

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