Discovery of a Plant 14-3-3 Inhibitor Possessing Isoform Selectivity and In Planta Activity

  • Angew Chem Int Ed Engl. 2024 Apr 24:e202400218. doi: 10.1002/anie.202400218.
Kotaro Nishiyama  1 ,  Yusuke Aihara  2  3 ,  Takehiro Suzuki  1 ,  Koji Takahashi  2  4 ,  Toshinori Kinoshita  2  4 ,  Naoshi Dohmae  1 ,  Ayato Sato  2 ,  Shinya Hagihara  1  2
Affiliations
  • 1. Center for Sustainable Resource Science, RIKEN, 2-1 Hirosawa, Wako City, Saitama, 351-0198, Japan.
  • 2. Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University Chikusa, Nagoya, 464-8602, Japan.
  • 3. PRESTO, Japan Science and Technology Agency (JST), Honcho 4-1-8, Kawaguchi, Saitama, 332-0012, Japan.
  • 4. Graduate School of Science, Nagoya University Chikusa, Nagoya, 464-8602, Japan.
PMID: 38658314 DOI: 10.1002/anie.202400218
Abstract

Synthetic modulators of plant 14-3-3s are promising chemical tools both for understanding the 14-3-3-related signaling pathways and controlling plant physiology. Herein, we describe a novel small-molecule inhibitor for 14-3-3 proteins of Arabidopsis thaliana. The inhibitor was identified from unexpected products in a stock solution in dimethyl sulfoxide (DMSO) of an in-house chemical library. Mass spectroscopy, mutant-based analyses, fluorescence polarization assays, and thermal shift assays revealed that the inhibitor covalently binds to an allosteric site of 14-3-3 with isoform selectivity. Moreover, infiltration of the inhibitor to Arabidopsis leaves suppressed the stomatal aperture. The inhibitor should provide new insight into the design of potent and isoform-selective 14-3-3 modulators.

Keywords
14-3-3 inhibitors; Arabidopsis thaliana; Isoform-selective inhibition; Protein-protein interactions; Stomata.
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