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.
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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.).
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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.
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Takeuchi, J., Okamoto, M., Akiyama, T. et al. Designed abscisic acid analogs as antagonists of PYL-PP2C receptor interactions. Nat Chem Biol 10, 477–482 (2014). https://doi.org/10.1038/nchembio.1524
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DOI: https://doi.org/10.1038/nchembio.1524
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