title: Designed abscisic acid analogs as antagonists of PYL-PP2C receptor interactions.
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.
authors.affiliation: 1] Graduate School of Science and Technology, Shizuoka University, Shizuoka, Japan. [2].
authors.forename: Jun
authors.initials: J
authors.lastname: Takeuchi
authors.affiliation: 1] Arid Land Research Center, Tottori University, Tottori, Japan. [2] Department of Botany and Plant Sciences and Center for Plant Cell Biology, University of California-Riverside, Riverside, California, USA. [3].
authors.forename: Masanori
authors.initials: M
authors.lastname: Okamoto
authors.affiliation: Department of Bioscience, Tokyo University of Agriculture, Tokyo, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Akiyama
authors.affiliation: Graduate School of Agriculture, Shizuoka University, Shizuoka, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Muto
authors.affiliation: Department of Bioscience, Tokyo University of Agriculture, Tokyo, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Yajima
authors.affiliation: Department of Applied Biology and Chemistry, Tokyo University of Agriculture, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sue
authors.affiliation: RIKEN Center for Sustainable Resource Science, Kanagawa, Japan.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Seo
authors.affiliation: RIKEN Center for Sustainable Resource Science, Kanagawa, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kanno
authors.affiliation: National Institute for Agro-Environmental Sciences, Ibaraki, Japan.
authors.forename: Tsunashi
authors.initials: T
authors.lastname: Kamo
authors.affiliation: 1] Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada. [2].
authors.forename: Akira
authors.initials: A
authors.lastname: Endo
authors.affiliation: Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Eiji
authors.initials: E
authors.lastname: Nambara
authors.affiliation: Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Hirai
authors.affiliation: 1] Graduate School of Agriculture, Shizuoka University, Shizuoka, Japan. [2] Research Institute of Green Science and Technology, Shizuoka University, Shizuoka, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ohnishi
authors.affiliation: Department of Botany and Plant Sciences and Center for Plant Cell Biology, University of California-Riverside, Riverside, California, USA.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Cutler
authors.affiliation: 1] Graduate School of Science and Technology, Shizuoka University, Shizuoka, Japan. [2] Graduate School of Agriculture, Shizuoka University, Shizuoka, Japan. [3] Research Institute of Green Science and Technology, Shizuoka University, Shizuoka, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Todoroki
mesh_terms: D000040:Abscisic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D017360:Arabidopsis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029681:Arabidopsis Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018525:Germination / Q000187:drug effects; D018545:Lactuca / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010937:Plant Growth Regulators / Q000138:chemical synthesis / Q000494:pharmacology; D018521:Plant Physiological Phenomena; D011485:Protein Binding; D031224:Raphanus / Q000187:drug effects / Q000378:metabolism; D012639:Seeds / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D029681:Arabidopsis Proteins; D010937:Plant Growth Regulators; D000040:Abscisic Acid; D010749:Phosphoprotein Phosphatases