TY - JOUR
T1 - Structure-Based Chemical Design of Abscisic Acid Antagonists That Block PYL-PP2C Receptor Interactions
AU - Takeuchi, Jun
AU - Mimura, Naoki
AU - Okamoto, Masanori
AU - Yajima, Shunsuke
AU - Sue, Masayuki
AU - Akiyama, Tomonori
AU - Monda, Keina
AU - Iba, Koh
AU - Ohnishi, Toshiyuki
AU - Todoroki, Yasushi
N1 - Funding Information:
We thank T. Nakagawa for providing pGWB vectors, E. Nambara and A. Endo for providing promoter MAPKKK18::-GUS transgenic Arabidopsis seeds, and Toray Industries Inc., Tokyo, Japan, for the gift of (+)-ABA. We also thank Edanz Group (www.edanzediting.com) for editing a draft of this manuscript. This work was supported in part by the Japanese Society for the Promotion of Science (JSPS) KAKENHI (16H06848 to J.T., 17H05009 to M.O., 16H07045 to K.M., 26221103 to K. I.), JST (JPMJPR15Q5 to M.O.), and CREST (JPMJCR15O5 to K.I.).
PY - 2018/5/18
Y1 - 2018/5/18
N2 - 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.
AB - 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.
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U2 - 10.1021/acschembio.8b00105
DO - 10.1021/acschembio.8b00105
M3 - Article
C2 - 29620349
AN - SCOPUS:85047459397
SN - 1554-8929
VL - 13
SP - 1313
EP - 1321
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 5
ER -