Isothermal titration calorimetry instrumentation for structural biology, biological mechanisms and drug discovery

用于结构生物学、生物机制和药物发现的等温滴定量热仪

• 批准号: BB/T01752X/1
• 负责人: Maria R Conte
• 金额: $ 24.68万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT01752X%2F1
• 关键词: Isothermal; titration; calorimetry; instrumentation; structural

Biomolecular interactions and characterisations form the basis of a plethora of research projects at King's, from fundamental investigations of molecular mechanisms to more applied research with medical and social impact. There is an increasing need to improve the precision and accuracy of these characterisations to achieve a detailed understanding of health and disease pathways and mechanisms, to facilitate the translation of this science towards outcomes that will benefit society. One of the key techniques used for such investigations is isothermal titration calorimetry (ITC), which provides a universal approach to study in detail how molecules are able to interact with one another, for example to understand which potential drug is able to block its target more efficiently, how bacteria develop resistance to antibiotics, or to explain the fundamental bases of life. For the many groups at King's, spread across four Faculties, there is a clear and urgent demand to improve upon the results that we can currently produce, and enable the characterisation and/or identification of new biochemical reactions or molecular assemblies that play a key role in a number of fields, including host-pathogen interactions, natural product biosynthesis, ageing, cardiovascular research, cancer, chemical biology and bioengineering, neurological disorders, signalling pathways, asthma and allergy. The instrumentation requested here holds promise of transforming the science of a wide user-base community at King's. King's is a leading international research institution across a range of biological disciplines, thus the potential for this investment of local provision of ITC instrumentation to add value is enormous. The ITC instrumentations will be part of the Wellcome Trust-supported Centre for Biomolecular Spectroscopy and will operate in synergy with other methodologies, integrating with other biophysical and structural biology methods and promoting exchanges with other in-house infrastructure and platforms (e.g. mass spectrometry, 'omics' platforms, imaging). The setting within the Centre will also facilitate usage by researchers from other academic institutions and/or industries, widening the breadth of the science that will be performed. Equipped with the latest ITC instrumentation, the Centre will contribute to the elucidation of molecular mechanisms of fundamental bioscience and permit state-of-the-art characterisation of biological therapeutics, to tackle strategic challenges in line with the BBSRC remit and priorities. The new instrument will strengthen the strategic mission of the Centre for Biomolecular Spectroscopy to deliver the highest quality data for internationally competitive research, train new generations of scientists in cutting edge methodologies, promote exchange of ideas and foster new interdisciplinary approaches (with academia and industries) for solving fundamental biological questions, addressing new therapeutic and societal challenges and providing benefits for human health.

生物分子相互作用和表征形成了国王学院大量研究项目的基础，从分子机制的基础研究到具有医学和社会影响的应用研究。越来越需要提高这些特征的精确度和准确性，以详细了解健康和疾病的途径和机制，促进这一科学转化为有益于社会的成果。用于此类研究的关键技术之一是等温滴定量热法（ITC），它提供了一种通用方法来详细研究分子如何相互作用，例如了解哪种潜在药物能够更有效地阻断其靶标，细菌如何对抗生素产生耐药性，或解释生命的基本基础。对于国王的许多团体，分布在四个学院，有一个明确和迫切的需求，以改善我们目前可以产生的结果，并使新的生化反应或分子组装的表征和/或识别在许多领域发挥关键作用，包括宿主-病原体相互作用，天然产物生物合成，衰老，心血管研究，癌症，化学生物学和生物工程，神经系统疾病、信号通路、哮喘和过敏。这里要求的仪器有望改变国王学院广泛的用户群社区的科学。King's是一家领先的国际研究机构，横跨一系列生物学科，因此，在当地提供ITC仪器的投资具有巨大的增值潜力。ITC仪器将成为Wellcome Trust支持的生物分子光谱学中心的一部分，并将与其他方法协同运作，与其他生物物理和结构生物学方法相结合，并促进与其他内部基础设施和平台（例如质谱，“组学”平台，成像）的交流。中心内的环境也将促进来自其他学术机构和/或行业的研究人员的使用，扩大将进行的科学的广度。该中心配备了最新的ITC仪器，将有助于阐明基础生物科学的分子机制，并允许最先进的生物疗法表征，以应对符合BBSRC职权范围和优先事项的战略挑战。新仪器将加强生物分子光谱学中心的战略使命，为具有国际竞争力的研究提供最高质量的数据，培训新一代科学家掌握尖端方法，促进思想交流，并促进新的跨学科方法（与学术界和工业界）解决基本的生物学问题，应对新的治疗和社会挑战，并为人类健康提供好处。

项目成果

Discovery of novel cardiac troponin activators using fluorescence polarization-based high throughput screening assays.

• DOI: 10.1038/s41598-023-32476-w
• 发表时间: 2023-03-30
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Parijat, Priyanka;Ponnam, Saraswathi;Attili, Seetharamaiah;Campbell, Kenneth S.;El-Mezgueldi, Mohammed;Pfuhl, Mark;Kampourakis, Thomas
• 通讯作者: Kampourakis, Thomas

When is an obscurin variant pathogenic? The impact of Arg4344Gln and Arg4444Trp variants on protein-protein interactions and protein stability.

• DOI: 10.1093/hmg/ddab010
• 发表时间: 2021-06-09
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Fukuzawa A;Koch D;Grover S;Rees M;Gautel M
• 通讯作者: Gautel M

Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload.

• DOI: 10.7554/elife.58313
• 发表时间: 2021-09-24
• 期刊: eLife
• 影响因子: 7.7
• 作者: Filomena MC;Yamamoto DL;Carullo P;Medvedev R;Ghisleni A;Piroddi N;Scellini B;Crispino R;D'Autilia F;Zhang J;Felicetta A;Nemska S;Serio S;Tesi C;Catalucci D;Linke WA;Polishchuk R;Poggesi C;Gautel M;Bang ML
• 通讯作者: Bang ML

A thiol redox sensor in soluble epoxide hydrolase enables oxidative activation by intra-protein disulfide bond formation.

可溶性环氧化物水解酶中的硫醇氧化还原传感器可以通过蛋白质二硫键形成氧化激活。

• DOI: 10.1016/j.redox.2021.102107
• 发表时间: 2021-10
• 期刊: Redox biology
• 影响因子: 11.4
• 作者: Charles RL;Abis G;Fernandez BF;Guttzeit S;Buccafusca R;Conte MR;Eaton P
• 通讯作者: Eaton P

Structural basis of dimerization and nucleic acid binding of human DBHS proteins NONO and PSPC1.

• DOI: 10.1093/nar/gkab1216
• 发表时间: 2022-01-11
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Knott GJ;Chong YS;Passon DM;Liang XH;Deplazes E;Conte MR;Marshall AC;Lee M;Fox AH;Bond CS
• 通讯作者: Bond CS