Next generation auxins and anti-auxins : principles for binding and design

下一代生长素和抗生长素：结合和设计原理

基本信息

批准号：
BB/L010623/1
负责人：
Stefan Kepinski
金额：
$ 45.68万
依托单位：
University of Leeds
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FL010623%2F1
关键词：
Next generation auxins anti principles

项目摘要

Context: Plant growth and development are dynamically controlled by hormones. Hormones are mobile signalling molecules which coordinate growth in response to environmental cues. Auxin is a hormone and is involved in almost every part of a plant's life, from embryo to wood. In order for auxin to trigger responses it needs a receptor, a protein to which it binds in a very specific and defined way. Auxin binding acts as a molecular switch, initiating a chain of events that leads to changes in which whole groupings of the plant's genes are switched on or off to change developmental decisions. We have been studying a protein called TIR1 as an auxin receptor, along with members of its family called AFB proteins. We have shown that some auxins (there are many) are selective for one or other receptor family member.Aims and objectives: This proposal describes a set of experiments that allows us to specify and quantify the changes between family members. In turn, this allows us to describe the special features on each type of auxin which determine specificity and allows us to start to understand the molecular rules defining this specificity. Auxins are also valuable agrochemicals. In their main application as herbicides they already present a certain element of selectivity, killing broad-leaved weeds in preference to cereals. However, we now know that there are more layers of selectivity to be exploited. This makes it imperative that we learn much more detail about the rules of specificity if we are to design a new generation of selective plant growth regulators. Our project sets out a number of complimentary lines of experimentation to investigate in great detail the features which differentiate AFB5, for example, from TIR1. We will use the latest biophysical techniques to measure the speeds of binding and the energy changes on binding. By comparing these values and comparing them with computer-driven calculations of the auxin molecules themselves, we will be able to derive design features specific for each template. Further, we know that when auxin binds to its receptor, this interaction creates a binding site for a second protein, a co-receptor. We believe that the TIR1 receptor acts as an enzyme to modify the shape of the co-receptor during binding. We will investigate this hypothesis and add kinetic details of this second part of the co-receptor assembly into our molecular models. With the two primary stages completed, we will have a matrix of detailed information about what makes a molecule an auxin and how they are selective and we will use this as a platform for designing new auxins and anti-auxins. These will be made by colleagues and tested for efficacy and selectivity. Potential applications and benefits: Examples of agricultural use of auxins include treatments to flowers, fruits and nuts and as selective weedkillers to kill broadleaved plants, not cereals and grasses and are of great agricultural value. Up to now, millions of compounds have been made and screened to find the chemicals we use. This project will measure in fine detail the very special interactions made by auxins at their several, but specific target sites. From this information we will start to define rules for new and more selective auxinic agrochemicals because, so far, agriculture has exploited only auxin analogues. Our technologies will enable us to add selective auxin antagonists (anti-auxins) into the toolkit. The aim is to create a new generation of safe, selective and low dosage agricultural compounds.

环境：植物生长和发育由激素动态控制。激素是移动信号分子，可响应环境线索来协调生长。生长素是一种激素，几乎参与了植物生命的每个部分，从胚胎到木材。为了使生长素触发反应，它需要一个受体，它以非常特定和定义的方式结合的蛋白质。生长素结合起着分子开关的作用，引发了一系列事件，导致植物基因的整个分组开启或关闭以改变发育决策的变化。我们一直在研究一种称为TIR1作为生长素受体的蛋白质，以及其家族成员称为AFB蛋白。我们已经证明，一些生长素（有很多）是一个或其他受体家庭成员的选择性。iam和目标：该提案描述了一组实验，使我们能够指定和量化家庭成员之间的更改。反过来，这使我们能够描述每种类型的生长素上的特殊特征，这些特征决定了特异性，并使我们能够开始理解定义这种特异性的分子规则。生长素也是有价值的农产品。在作为除草剂的主要应用中，它们已经提出了一定的选择性元素，杀死了宽阔的杂草，而不是谷物。但是，我们现在知道有更多的选择性要利用。这必须使我们必须在设计新一代选择性植物生长调节器时了解更多有关特异性规则的详细信息。我们的项目规定了许多免费实验线，以详细研究将AFB5与TIR1区分开的特征。我们将使用最新的生物物理技术来衡量结合速度和结合时的能量变化。通过比较这些值并将它们与生长素分子本身的计算机驱动计算进行比较，我们将能够得出每个模板特有的设计功能。此外，我们知道，当生长素与其受体结合时，这种相互作用会为第二蛋白，共受体创建一个结合位点。我们认为，TIR1受体是一种酶，可以在结合过程中修饰共受体的形状。我们将研究这一假设，并将共受体组件的第二部分的动力学细节添加到我们的分子模型中。在完成两个主要阶段后，我们将拥有一个详细信息矩阵，内容涉及使分子成为生长素以及它们如何具有选择性的方式，我们将使用它作为设计新的生长素和抗助剂的平台。这些将由同事制作，并测试有效性和选择性。潜在的应用和好处：生长素的农业用途的例子包括对花，水果和坚果的处理，以及作为杀死阔叶植物的选择性除草剂，而不是谷物和草，并且具有很大的农业价值。到目前为止，已经制造并筛选了数百万种化合物，以找到我们使用的化学物质。该项目将详细介绍生长素在其几个但特定的目标站点上进行的非常特殊的交互。从这些信息中，我们将开始定义新的和更具选择性的植物农业化学物质的规则，因为到目前为止，农业仅利用了生长素类似物。我们的技术将使我们能够在工具包中添加选择性的生长素拮抗剂（抗助剂）。目的是创建新一代的安全，选择性和低剂量的农业化合物。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A fuzzy encounter complex precedes formation of the fully-engaged TIR1-Aux/IAA auxin co-receptor system

DOI：
10.1101/781922
发表时间：
2019-09
期刊：
bioRxiv
影响因子：
0
作者：
Sigurd Ramans Harborough;A. Kalverda;G. Thompson;M. Kieffer;M. Kubeš;M. Quareshy;V. Uzunova;J. Prusińska;Ken-ichiro Hayashi;R. Napier;I. Manfield;S. Kepinski
通讯作者：
Sigurd Ramans Harborough;A. Kalverda;G. Thompson;M. Kieffer;M. Kubeš;M. Quareshy;V. Uzunova;J. Prusińska;Ken-ichiro Hayashi;R. Napier;I. Manfield;S. Kepinski

Intrinsic disorder and conformational coexistence in auxin coreceptors.

DOI：
10.1073/pnas.2221286120
发表时间：
2023-10-03
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Ramans-Harborough, Sigurd;Kalverda, Arnout P.;Manfield, Iain W.;Thompson, Gary S.;Kieffer, Martin;Uzunova, Veselina;Quareshy, Mussa;Prusinska, Justyna M.;Roychoudhry, Suruchi;Hayashi, Ken-ichiro;Napier, Richard;del Genio, Charo;Kepinski, Stefan
通讯作者：
Kepinski, Stefan

The Tetrazole Analogue of the Auxin Indole-3-acetic Acid Binds Preferentially to TIR1 and Not AFB5.

生长素吲哚-3-乙酸的四唑类似物优先与 TIR1 结合，而不与 AFB5 结合。