Serum Albumin: Binding and Transport of Pharmaceuticals and Functional Differences Derived from Divergent Evolution Characterized by Electron Paramagnetic Resonance (EPR) Spectroscopy
血清白蛋白:药物的结合和运输以及电子顺磁共振 (EPR) 光谱表征的发散进化所产生的功能差异
基本信息
- 批准号:257288979
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Grants
- 财政年份:2014
- 资助国家:德国
- 起止时间:2013-12-31 至 2018-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Building on an EPR (electron paramagnetic resonance)-based research platform recently developed for the study of serum albumins, this proposal has two major objectives that are interconnected. The first goal is to understand structural plasticity and dynamics of serum albumin (human and animal, e.g. bovine) when binding small pharmaceutically active molecules and when interacting with a membrane. This will be achieved using EPR spectroscopy and will help bridging the gap between fundamental structural biology-related research on albumin and its medical implications. Nine different pharmacologically important classes of drugs have been identified beforehand that shall be studied in this part of the project. These classes are: 1) Analgetics (drugs for pain relief), 2) Anticoagulants; 3) Narcotics; 4) Uricostatics (prevention of kidney stones); 5) Uricosurics (gout medication); 6) Cytostatics; 7) Steroids (hormones); 8) Vitamins; 9) Antiauxins. The binding of these spin-labeled drugs to albumin by EPR spectroscopy and other physical techniques (e.g. isothermal titration calorimetry, ITC) is then characterized. Furthermore, changes in plasticity of albumins (human) as derived from pulse EPR (DEER) measurements when ligands are bound are characterized. This includes understanding allosteric effects of concurrent binding of drugs and fatty acids. Then the study aims at exploring interactions of (drug-, fatty-acid-)loaded (human, bovine) albumins with artificial membranes and the ensuing changes in structure/plasticity of the protein. This will be achieved by a combination of EPR spectroscopic methods and surface-sensitive infrared reflection-absorption spectroscopy (IRRAS). The second big aim of this proposal is to understand the structure-function relationship of six different mammal albumins and how differences in structure, plasticity and function of albumins (human and animal) may have arisen. This part thus aims at connecting the evolution of albumins with the difference in solution structural plasticity. The proposal hence is to 'follow evolution with EPR': Use the EPR-spectroscopic research platform for characterizing albumin solution structure to find out where in the divergent evolution from a common mammal ancestor the plasticity of albumin surface (as seen in HSA) has emerged. Then it is studied how much sequence identity with HSA is necessary to display this plasticity and which amino acids, mostly on the surface of the proteins, are important to switch from static (BSA) to plastic (HSA). Moving from this point, it is then characterized how differences in plasticity translate into functional differences, e.g. in uptake, release or transport of ligands. Finally, it is investigated how posttranslational modification of albumins alters the structure-function relationship.
建立在EPR(电子顺磁共振)为基础的研究平台,最近开发的血清白蛋白的研究,这一建议有两个相互关联的主要目标。第一个目标是了解血清白蛋白(人和动物,例如牛)结合小的药物活性分子时和与膜相互作用时的结构可塑性和动力学。这将实现使用EPR光谱,并将有助于弥合白蛋白的基础结构生物学相关研究及其医学意义之间的差距。已经预先确定了九种不同的、非常重要的毒品类别,将在项目的这一部分进行研究。这些类是:1)镇痛药(止痛药); 2)抗凝剂; 3)麻醉剂; 4)尿酸抑制剂(预防肾结石); 5)尿酸排泄剂(痛风药物); 6)细胞抑制剂; 7)类固醇(激素); 8)维生素; 9)抗生长素。然后通过EPR光谱和其他物理技术(例如等温滴定量热法,ITC)表征这些自旋标记药物与白蛋白的结合。此外,白蛋白(人)的可塑性的变化,从脉冲EPR(DEER)测量时,配体结合的特点。这包括了解药物和脂肪酸同时结合的变构效应。然后,该研究旨在探索(药物,脂肪酸)加载(人,牛)白蛋白与人工膜的相互作用和随之而来的蛋白质的结构/可塑性的变化。这将通过EPR光谱方法和表面敏感红外反射吸收光谱(IRRAS)的组合来实现。该提案的第二大目标是了解六种不同哺乳动物白蛋白的结构-功能关系,以及白蛋白(人类和动物)的结构,可塑性和功能差异如何产生。因此,本部分旨在将白蛋白的进化与溶液结构可塑性的差异联系起来。因此,该建议是“用EPR跟踪进化”:使用EPR光谱研究平台来表征白蛋白溶液结构,以找出在从共同哺乳动物祖先的分化进化中,白蛋白表面的可塑性(如在HSA中所见)出现的地方。然后研究了与HSA有多少序列同一性是显示这种可塑性所必需的,以及哪些氨基酸(主要在蛋白质的表面上)对于从静态(BSA)切换到塑性(HSA)是重要的。从这一点出发,然后表征可塑性的差异如何转化为功能差异,例如配体的摄取,释放或转运。最后,研究了白蛋白的翻译后修饰如何改变其结构与功能的关系。
项目成果
期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Probing the Nanoscopic Thermodynamic Fingerprint of Paramagnetic Ligands Interacting with Amphiphilic Macromolecules
探索顺磁性配体与两亲性大分子相互作用的纳米热力学指纹
- DOI:10.3390/polym9080324
- 发表时间:2017
- 期刊:
- 影响因子:5
- 作者:Jörg Reichenwallner;Christian Schwieger;Dariush Hinderberger
- 通讯作者:Dariush Hinderberger
Ligand-Binding Cooperativity Effects in Polymer-Protein Conjugation.
聚合物-蛋白质缀合中的配体结合协同效应
- DOI:10.1021/acs.biomac.9b00016
- 发表时间:2019
- 期刊:
- 影响因子:6.2
- 作者:Jörg Reichenwallner;Anja Thomas;Tobias Steinbach;Jana Eisermann;Christian E. H. Schmelzer;Frederik Wurm;Dariush Hinderberger
- 通讯作者:Dariush Hinderberger
Exploring the pH-Induced Functional Phase Space of Human Serum Albumin by EPR Spectroscopy
- DOI:10.3390/magnetochemistry4040047
- 发表时间:2018-12-01
- 期刊:
- 影响因子:2.7
- 作者:Reichenwallner, Joerg;Oehmichen, Marie-T.;Hinderberger, Dariush
- 通讯作者:Hinderberger, Dariush
Tunable dynamic hydrophobic attachment of guest molecules in amphiphilic core–shell polymers
两亲性核壳聚合物中客体分子的可调节动态疏水附着
- DOI:10.1039/c6py01335j
- 发表时间:2016
- 期刊:
- 影响因子:4.6
- 作者:Jörg Reichenwallner;Anja Thomas;Lutz Nuhn;Tobias Johann;Annette Meister;Holger Frey;Dariush Hinderberger
- 通讯作者:Dariush Hinderberger
Fatty Acid Triangulation in Albumins Using a Landmark Spin Label
- DOI:10.1002/ijch.201900073
- 发表时间:2019-11-18
- 期刊:
- 影响因子:3.2
- 作者:Reichenwallner, Joerg;Haucnschild, Till;Hinderberger, Dariush
- 通讯作者:Hinderberger, Dariush
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Professor Dr. Dariush Hinderberger其他文献
Professor Dr. Dariush Hinderberger的其他文献
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{{ truncateString('Professor Dr. Dariush Hinderberger', 18)}}的其他基金
Characterizing the Effect of Substitutions Mimicking Deimination and Phosphorylation of 18.5-kDa Myelin Basic Protein (MBP) on its Structure and Dynamics in Myelin-Like Membranes
表征模拟 18.5-kDa 髓磷脂碱性蛋白 (MBP) 脱亚胺化和磷酸化的取代对其在髓磷脂样膜中的结构和动态的影响
- 批准号:
320907857 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Research Grants
Untersuchung molekularer Selbstorganisation durch elektrostatische Wechselwirkungen mittels Elektronen-Spin-Resonanz (ESR)-Spektroskopie
使用电子自旋共振 (ESR) 光谱研究通过静电相互作用的分子自组织
- 批准号:
49742554 - 财政年份:2007
- 资助金额:
-- - 项目类别:
Research Grants
Untersuchung des Methan-herstellenden Enzyms Methyl-Koenzym-M-Reduktase mittels EPR-Spektroskopie
使用 EPR 光谱研究产甲烷酶甲基辅酶 M 还原酶
- 批准号:
5440006 - 财政年份:2004
- 资助金额:
-- - 项目类别:
Research Fellowships
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Grant-in-Aid for Challenging Exploratory Research
Preventing Kernicterus: Serum Albumin-Bilirubin Binding
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- 批准号:
7613740 - 财政年份:2008
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