Rational Design of an Auxin Antagonist of the SCFTIR1 Auxin Receptor Complex
Rational Design of an Auxin Antagonist of the SCFTIR1 Auxin Receptor Complex
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DOI：
10.1021/cb200404c
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发表时间：
2012-03-01
影响因子：
4
通讯作者：
Nozaki, Hiroshi
中科院分区：
文献类型：
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作者：
Hayashi, Ken-ichiro;Neve, Joshua;Nozaki, Hiroshi
植物激素生长素是植物生长和发育的主要调节剂。通过调节细胞分裂和伸长的速率并触发特定的模式事件，吲哚 3-乙酸 (IAA) 几乎调节植物发育的各个方面。生长素的感知涉及三元复合物的形成，该三元复合物由生长素受体 TIR1/AFB 家族的 F-box 蛋白、生长素分子和辅助抑制蛋白 Aux/IAA 家族的成员组成。在这项研究中，我们通过计算机虚拟筛选确定了一种有效的生长素拮抗剂 α-(苯乙基-2-氧代)-IAA，作为 TIR1/AFB 受体的先导化合物。该分子被用作开发更有效的 TIR1 拮抗剂 auxinole（α-[2,4-二甲基苯基乙基-2-oxo]-IAA）的基础，采用基于结构的药物设计方法。 Auxinole 结合 TIR1，阻断 TIR1 IAA Aux/IAA 复合物的形成，从而抑制生长素响应基因的表达。分子对接分析表明，auxinole 中的苯环会与 TIR1 的 Phe82 发生强烈相互作用，TIR1 的 Phe82 对 Aux/IAA 识别至关重要。与这种预测的作用模式一致，辅助素竞争性抑制植物中的各种辅助素反应。此外，辅助素可阻断小立碗藓的生长素反应，表明其活性遍及多种物种。我们的工作不仅证实了化学工具在植物生物学中的实用性，而且还展示了一种新型的蛋白质-蛋白质相互作用的小分子抑制剂，这对于其他植物激素（例如茉莉酸、赤霉素和脱落酸）的感知机制是常见的。
The plant hormone auxin is a master regulator of plant growth and development. By regulating rates of cell division and elongation and triggering specific patterning events, indole 3-acetic acid (IAA) regulates almost every aspect of plant development. The perception of auxin involves the formation of a ternary complex consisting of an F-box protein of the TIR1/AFB family of auxin receptors, the auxin molecule, and a member the Aux/IAA family of co-repressor proteins. In this study, we identified a potent auxin antagonist, alpha-(phenylethyl-2-oxo)-IAA, as a lead compound for TIR1/AFB receptors by in silico virtual screening. This molecule was used as the basis for the development of a more potent TIR1 antagonist, auxinole (alpha-[2,4-dimethylphenylethyl-2-oxo]-IAA), using a structure-based drug design approach. Auxinole binds TIR1 to block the formation of the TIR1 IAA Aux/IAA complex and so inhibits auxin-responsive gene expression. Molecular docking analysis indicates that the phenyl ring in auxinole would strongly interact with Phe82 of TIR1, a residue that is crucial for Aux/IAA recognition. Consistent with this predicted mode of action, auxinole competitively inhibits various auxin responses in planta. Additionally, auxinole blocks auxin responses of the moss Physcomitrella patens, suggesting activity over a broad range of species. Our works not only substantiates the utility of chemical tools for plant biology but also demonstrates a new class of small molecule inhibitor of protein-protein interactions common to mechanisms of perception of other plant hormones, such as jasmonate, gibberellin, and abscisic acid.