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通过 ACT-Like 结构域干扰主调控 bHLH 异源二聚体来抑制气孔分化的化学抑制。

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

机构信息

Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Nagoya, Aichi, Japan.

Howard Hughes Medical Institute, The University of Texas at Austin, Austin, TX, USA.

出版信息

Nat Commun. 2024 Oct 23;15(1):8996. doi: 10.1038/s41467-024-53214-4.

DOI:10.1038/s41467-024-53214-4
PMID:39443460
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11500415/
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.

摘要

利用化合物选择性干扰蛋白质相互作用，可以剖析和控制发育过程。气孔的分化是植物生长和存活所必需的细胞瓣膜，由碱性螺旋-环-螺旋（bHLH）异二聚体决定。利用一种新的胺化反应，我们在此报告了一种非典型的双磺化咪唑啉酮，Stomidazolone 的合成、衍生化、靶标鉴定和作用模式，它能触发气孔干细胞停滞。我们的正向化学遗传学分析结合生物物理分析表明，Stomidazolone 能直接与调控气孔分化的主调控因子 MUTE 的 C 端 ACT-Like（ACTL）结构域结合，并在体外和植物细胞中干扰其与伴侣 bHLH 蛋白 SCREAM 的异二聚化。另一方面，生物活性较低的 Stomidazolone 类似物不能与 MUTE 结合或破坏 SCREAM-MUTE 异二聚体。根据结构对接建模，我们合理设计了结合能力降低的 MUTE。这些工程化的 MUTE 蛋白完全具有功能，并在体内赋予 Stomidazolone 抗性。我们的研究将双磺化咪唑啉酮鉴定为气孔主调控因子的直接抑制剂，进一步扩展了用于干扰 bHLH-ACTL 蛋白以操纵植物发育的化学空间。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/face/11500415/d7efa3d2ba28/41467_2024_53214_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/face/11500415/7a09b706aded/41467_2024_53214_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/face/11500415/3091d2bc617e/41467_2024_53214_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/face/11500415/a2f5a0b70c97/41467_2024_53214_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/face/11500415/d7efa3d2ba28/41467_2024_53214_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/face/11500415/7a09b706aded/41467_2024_53214_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/face/11500415/9307da82d829/41467_2024_53214_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/face/11500415/cbc4da19c033/41467_2024_53214_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/face/11500415/c9dd0a02c1e8/41467_2024_53214_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/face/11500415/3091d2bc617e/41467_2024_53214_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/face/11500415/a2f5a0b70c97/41467_2024_53214_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/face/11500415/d7efa3d2ba28/41467_2024_53214_Fig7_HTML.jpg

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