Probing drug receptor binding sites driven by solid state NMR - An interdisciplinary approach.

由固态 NMR 驱动的药物受体结合位点探测 - 一种跨学科方法。

• 批准号: EP/E000177/1
• 负责人: Chris Willis
• 金额: $ 51.54万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FE000177%2F1
• 关键词: Probing; drug; receptor; binding; sites

Biology works through highly synchronised chemical interactions at the atomistic scale. Small changes in the electronic charge of a biological molecule, or even the position of a hydrogen atom can have far-reaching consequences (e.g. the very contrasting actions of two subtly different forms (alpha, beta) of thalidomide, or a change of one amino acid in haemoglobin causing sickle cell anaemia). Such subtleties are becoming better understood at the molecular level, but still much is to be discovered and understood for promotion of health and well-being. The major class of targets in disease control for the next ten years is membrane proteins. These are a cell's first point of contact with the outside world and about 85% of all signals to the cell are transmitted through the membrane. It is not surprising then that both academics and drug companies are interested in how such signals are transmitted into the cell (2 Nobel prizes were awarded in 2005 for the revelation that one target membrane protein can activate and signal a multitude of other proteins, depending upon the nature of the small molecule activation, and over 10 Nobel prizes have been awarded for membrane protein studies since 1987). Membrane proteins are very difficult to work with, which is why there are only 21 structures (out of millions available) in the data bases. In addition, we do not have the structure of any ligand-activated human receptor. What we now need is a detailed insight into how these signals are initiated and transmitted at the molecular level, and this can be addressed using nuclear magnetic resonance (NMR) methods designed specifically for probing the detail at very high resolution (better than 0.03 nanometres) and with electronic and dynamic details but, very importantly, in the absence of the total structure of the target receptor protein.Solid state NMR exploits specifically the magnetic properties of some specific atoms for large heterogeneous, non-ordered macromolecules - this has been a fast growing area in structural biology and the UK is at the forefront of the developments. An essential part of this work is the incorporation of magnetic spies (or labels) into the molecule of interest so that we can obtain the information required. The chemical insertion of monitoring nuclei into the information-rich position in the macromolecule is vital and a pre-requisite and can only come from state-of-the-art clever chemistry directed at answering biologically important questions using physical methods. The NMR method is unique in producing very localized and highly specific information at a information-rich site, but this is only possible through the use of highly specialised chemistry to make molecules with the NMR labels where needed - hence this funding application will combine these two areas of expertise (NMR at Oxford and labelling at Bristol) to answer the important biological question How do small molecules activate proteins to transmit signals into a cell? . Detailed information gained will facilitate the understanding of, e.g. how a hormone causes a particular response, or how a toxic chemical initiates cell death. Importantly for wealth creation for the UK, which traditionally has been highly successful in discovering drugs, new design principles will be elucidated.

生物学通过原子尺度上高度同步的化学相互作用发挥作用。生物分子电荷的微小变化，甚至氢原子位置的微小变化都可能产生深远的影响（例如，沙利度胺的两种细微不同形式（α、β）的截然不同的作用，或一个氨基的变化血红蛋白中的酸导致镰状细胞性贫血）。这些微妙之处在分子水平上得到了更好的理解，但为了促进健康和福祉，还有很多东西有待发现和理解。未来十年疾病控制的主要目标是膜蛋白。这些是细胞与外界的第一个接触点，大约 85% 的细胞信号是通过细胞膜传输的。因此，学术界和制药公司都对这些信号如何传递到细胞中感兴趣也就不足为奇了（2005 年，两项诺贝尔奖因揭示一种靶膜蛋白可以激活多种其他蛋白质并发出信号而获得诺贝尔奖，具体取决于小分子激活的本质，自 1987 年以来，已有 10 多个诺贝尔奖因膜蛋白研究而获得）。膜蛋白很难处理，这就是为什么数据库中只有 21 个结构（数百万个可用结构）。此外，我们没有任何配体激活的人类受体的结构。我们现在需要的是详细了解这些信号如何在分子水平上启动和传输，这可以使用专为以非常高分辨率（优于 0.03 纳米）探测细节而设计的核磁共振 (NMR) 方法来解决。并具有电子和动态细节，但非常重要的是，在缺乏目标受体蛋白的总结构的情况下。固态核磁共振专门利用一些特定原子的磁性来分析大的异质、无序大分子——这是一种快速的方法结构生物学领域不断发展，而英国处于发展的前沿。这项工作的一个重要部分是将磁性间谍（或标签）合并到感兴趣的分子中，以便我们可以获得所需的信息。将监测核以化学方式插入大分子中信息丰富的位置是至关重要的，也是先决条件，并且只能来自最先进的巧妙化学，旨在使用物理方法回答重要的生物学问题。 NMR 方法的独特之处在于，可以在信息丰富的地点生成非常本地化和高度具体的信息，但这只有通过使用高度专业化的化学方法来在需要的地方制造带有 NMR 标签的分子才有可能 - 因此，本次资助申请将结合这两种方法专业领域（牛津的核磁共振和布里斯托尔的标记）来回答重要的生物学问题小分子如何激活蛋白质以将信号传递到细胞中？ 。获得的详细信息将有助于理解，例如激素如何引起特定反应，或有毒化学物质如何引发细胞死亡。对于传统上在发现药物方面非常成功的英国来说，新的设计原则将得到阐明，这对于创造财富来说很重要。

项目成果

Convergent syntheses of 3,6-dihydroxydec-4-enolides.

3,6-二羟基癸-4-烯内酯的收敛合成。

• DOI: 10.1021/ol3018566
• 发表时间: 2012-07-31
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: Jonathan C Killen;Lorraine C. Axford;Sarah E. Newberry;T. J. Simpson;C. Willis
• 通讯作者: C. Willis

Recognition of intermediate functionality by acyl carrier protein over a complete cycle of fatty acid biosynthesis.

酰基载体蛋白在脂肪酸生物合成的完整循环中识别中间功能。

• DOI: http://dx.10.1016/j.chembiol.2010.05.024
• 发表时间: 2010
• 期刊: Chemistry & biology
• 作者: Ploskon E

Enantioselective syntheses of alpha-Fmoc-Pbf-[2-(13)C]-L-arginine and Fmoc-[1,3-(13)C2]-L-proline and Incorporation into the neurotensin receptor 1 ligand, NT(8-13).

α-Fmoc-Pbf-[2-(13)C]-L-精氨酸和 Fmoc-[1,3-(13)C2]-L-脯氨酸的对映选择性合成并掺入神经降压素受体 1 配体 NT(8

• DOI: http://dx.10.1021/jo9014497
• 发表时间: 2009
• 期刊: The Journal of organic chemistry
• 作者: Song C

Solution- and solid-state NMR studies of GPCRs and their ligands.

GPCR 及其配体的溶液和固态 NMR 研究。

• DOI: http://dx.10.1016/j.bbamem.2010.10.003
• 发表时间: 2011
• 期刊: Biochimica et biophysica acta
• 作者: Tapaneeyakorn S

In vitro kinetic study of the squalestatin tetraketide synthase dehydratase reveals the stereochemical course of a fungal highly reducing polyketide synthase.

角鲨他汀四酮合酶脱水酶的体外动力学研究揭示了真菌高度还原聚酮合酶的立体化学过程。

• DOI: 10.1039/c6cc10172k
• 发表时间: 2017-01-31
• 期刊: Chemical communications
• 影响因子: 4.9
• 作者: Emma Liddle;A. Scott;Li;D. Ivison;T. J. Simpson;C. Willis;R. Cox
• 通讯作者: R. Cox