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.

生物学通过在原子量表上高度同步化学相互作用来工作。生物分子的电子电荷甚至氢原子的位置的微小变化都可能产生深远的后果（例如，丘里替胺的两种微妙形式（Alpha，beta）的非常对比的作用，或者在引起镰状细胞的血红蛋白中的一种氨基酸变化）。在分子水平上，这种微妙之处正在更好地理解，但是在促进健康和福祉方面仍被发现和理解很多。接下来的十年中，疾病控制中的主要目标是膜蛋白。这些是细胞与外界的第一个接触点，所有信号中约有85％通过膜传输。毫不奇怪的是，学者和制药公司都对这些信号如何传输到细胞都感兴趣（2005年获得了2个诺贝尔奖，这是因为一个靶向膜蛋白可以激活并发出许多其他蛋白质的启示，这取决于小分子激活的性质，并且在10个诺贝尔的性质上，在10份诺贝尔奖中获得了1987年的质膜蛋白质研究）。膜蛋白很难使用，这就是为什么数据库中只有21个结构（数百万可用的）。此外，我们没有任何配体激活的人体受体的结构。 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在一些大型异质，非订购的大分子的特定原子中 - 这是结构生物学的快速生长区域，英国处于发展的最前沿。这项工作的重要组成部分是将磁性间谍（或标签）掺入感兴趣的分子中，以便我们获得所需的信息。将核的化学插入到大分子中的信息丰富的位置中是至关重要的，并且是先决条件，只能来自旨在使用物理方法回答生物学上重要的问题的最先进的聪明的化学反应。 NMR方法在信息丰富的网站上生成非常本地化和高度特定的信息是独一无二的，但这只有通过使用高度专业的化学方法与需要的NMR标签制作分子可以在需要的地方制作分子 - 因此，此资金应用将结合这两个领域的专业知识领域（牛津的NMR和Bristol的NMR和Bristol的NMR），以回答重要的生物素材，使小蛋白质构成了一个型号，该型号是如何构成蛋白质的？ 。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，或者有毒化学物质如何引发细胞死亡。重要的是，对于英国创造财富，传统上一直在发现毒品方面非常成功，将阐明新的设计原则。

项目成果

Fusarochromene, a novel tryptophan-derived metabolite from Fusarium sacchari.

Fusarochromene，一种来自糖镰孢的新型色氨酸衍生代谢物。

• DOI: 10.1039/d0ob02031a
• 发表时间: 2021
• 期刊: Organic & biomolecular chemistry
• 影响因子: 3.2
• 作者: Marshall JW

Synthesis of isotopically labelled amino acids

同位素标记氨基酸的合成

• DOI: 10.1002/jlcr.1301
• 发表时间: 2007
• 期刊: Journal of Labelled Compounds and Radiopharmaceuticals
• 影响因子: 1.8
• 作者: Rees D

Recognition of extended linear and cyclised polyketide mimics by a type II acyl carrier protein.

• DOI: 10.1039/c5sc03864b
• 发表时间: 2016-03-01
• 期刊: Chemical science
• 影响因子: 8.4
• 作者: Dong X;Bailey CD;Williams C;Crosby J;Simpson TJ;Willis CL;Crump MP
• 通讯作者: Crump MP

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