Defining and Exploiting Hypersensitivity Hotspots to Facilitate Abscisic Acid Agonist Optimization.,ACS Chemical Biology

当前位置： X-MOL 学术 › ACS Chem. Biol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Defining and Exploiting Hypersensitivity Hotspots to Facilitate Abscisic Acid Agonist Optimization.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-01-29 , DOI: 10.1021/acschembio.8b00955
Dezi Elzinga _{1,

2} , Erin Sternburg _{1,

3} , Davide Sabbadin _{2,

4} , Michael Bartsch ₄ , Sang-Youl Park _{1,

2} , Aditya Vaidya _{1,

2} , Assaf Mosquna ₁ , Amita Kaundal ₁ , Sebastian Wendeborn ₄ , Mathilde Lachia ₄ , Fedor V Karginov _{1,

3} , Sean R Cutler _{1,

2}

Affiliation

Pyrabactin resistance 1 (PYR1) and related abscisic acid (ABA) receptors are new targets for manipulating plant drought tolerance. Here, we identify and use PYR1 hypersensitive mutants to define ligand binding hotspots and show that these can guide improvements in agonist potency. One hotspot residue defined, A160, is part of a pocket that is occupied by ABA's C6 methyl or by the toluyl methyl of the synthetic agonist quinabactin (QB). A series of QB analogues substituted at the toluyl position were synthesized and provide up to 10-fold gain in activity in vitro. Furthermore, we demonstrate that hypersensitive receptors can be used to improve the sensitivity of a previously described mammalian cell ABA-regulated transcriptional circuit by three orders of magnitude. Collectively, our data show that the systematic mapping of hypersensitivity sites in a ligand-binding pocket can help guide ligand optimization and tune the sensitivity of engineered receptors.

中文翻译：

定义和开发超敏反应热点，以促进脱落酸激动剂的优化。

吡菌素抗性1（PYR1）和相关的脱落酸（ABA）受体是操纵植物抗旱性的新目标。在这里，我们确定并使用PYR1超敏突变体来定义配体结合热点，并表明这些可以指导激动剂效能的提高。定义的一个热点残基为A160，它是ABA的C6甲基或合成激动剂奎那卡汀（QB）的甲苯甲基所占据的口袋的一部分。合成了一系列在甲苯基位置取代的QB类似物，它们在体外的活性提高了10倍。此外，我们证明，超敏受体可用于将先前描述的哺乳动物细胞ABA调控的转录电路的敏感性提高三个数量级。总的来说，

更新日期：2019-01-22

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南