Chemical inhibition of stomatal differentiation by perturbation of the master-regulatory bHLH heterodimer via an ACT-Like domain

Ayami Nakagawa, Krishna Mohan Sepuru, Shu Jan Yip, Hyemin Seo, Calvin M. Coffin, Kota Hashimoto, Zixuan Li, Yasutomo Segawa, Rie Iwasaki, Hiroe Kato, Daisuke Kurihara, Yusuke Aihara, Stephanie Kim, Toshinori Kinoshita, Kenichiro Itami, Soon-Ki Han, Kei Murakami () and Keiko U. Torii ()
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Ayami Nakagawa: Nagoya University
Krishna Mohan Sepuru: The University of Texas at Austin
Shu Jan Yip: Nagoya University
Hyemin Seo: The University of Texas at Austin
Calvin M. Coffin: The University of Texas at Austin
Kota Hashimoto: Kwansei Gakuin University
Zixuan Li: Kwansei Gakuin University
Yasutomo Segawa: Myodaiji
Rie Iwasaki: Nagoya University
Hiroe Kato: Nagoya University
Daisuke Kurihara: Nagoya University
Yusuke Aihara: Nagoya University
Stephanie Kim: The University of Texas at Austin
Toshinori Kinoshita: Nagoya University
Kenichiro Itami: Nagoya University
Soon-Ki Han: Nagoya University
Kei Murakami: Nagoya University
Keiko U. Torii: Nagoya University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Selective perturbation of protein interactions with chemical compounds enables dissection and control of developmental processes. Differentiation of stomata, cellular valves vital for plant growth and survival, is specified by the basic-helix-loop-helix (bHLH) heterodimers. Harnessing a new amination reaction, we here report a synthesis, derivatization, target identification, and mode of action of an atypical doubly-sulfonylated imidazolone, Stomidazolone, which triggers stomatal stem cell arrest. Our forward chemical genetics followed by biophysical analyses elucidates that Stomidazolone directly binds to the C-terminal ACT-Like (ACTL) domain of MUTE, a master regulator of stomatal differentiation, and perturbs its heterodimerization with a partner bHLH, SCREAM in vitro and in plant cells. On the other hand, Stomidazolone analogs that are biologically inactive do not bind to MUTE or disrupt the SCREAM-MUTE heterodimers. Guided by structural docking modeling, we rationally design MUTE with reduced Stomidazolone binding. These engineered MUTE proteins are fully functional and confer Stomidazolone resistance in vivo. Our study identifies doubly-sulfonylated imidazolone as a direct inhibitor of the stomatal master regulator, further expanding the chemical space for perturbing bHLH-ACTL proteins to manipulate plant development.

Date: 2024
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DOI: 10.1038/s41467-024-53214-4

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