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

• DOI: 10.1038/nchembio.1524
• Publication Date: 2014-05-04T20:18:25Z
• Authors: Jun Takeuchi; Masanori Okamoto; Tomonori Akiyama; Takuya Muto; Shunsuke Yajima; Masayuki Sue; Mitsunori Seo; Yuri Kanno; Tsunashi Kamo; Akira Endo; Eiji Nambara; Nobuhiro Hirai; Toshiyuki Ohnishi; Sean R Cutler; Yasushi Todoroki
• Keywords: Models, Molecular; 0303 health sciences; Arabidopsis Proteins; Arabidopsis; Germination; Raphanus; Structure-Activity Relationship; 03 medical and health sciences; Plant Growth Regulators; Seeds; Phosphoprotein Phosphatases; Plant Physiological Phenomena; Abscisic Acid; Lactuca; Protein Binding

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.