Czub Mateusz P, Stewart Alan J, Shabalin Ivan G, Minor Wladek
Department of Molecular Physiology and Biological Physics, University of Virginia, 1340 Jefferson Park Avenue, Charlottesville, VA 22908, USA.
Center for Structural Genomics of Infectious Diseases (CSGID), University of Virginia, 1340 Jefferson Park Avenue, Charlottesville, VA 22908, USA.
IUCrJ. 2022 Jul 16;9(Pt 5):551-561. doi: 10.1107/S2052252522006820. eCollection 2022 Sep 1.
Serum albumin is a circulatory transport protein that has a highly conserved sequence and structure across mammalian organisms. Its ligand-binding properties are of importance as albumin regulates the pharmacokinetics of many drugs. Due to the high degree of structural conservation between mammalian albumins, nonhuman albumins such as bovine serum albumin or animal models are often used to understand human albumin-drug interactions. Ketoprofen is a popular nonsteroidal anti-inflammatory drug that is transported by albumin. Here, it is revealed that ketoprofen exhibits different binding-site preferences when interacting with human serum albumin compared with other mammalian albumins, despite the conservation of binding sites across species. The reasons for the observed differences were explored, including identifying ketoprofen binding determinants at specific sites and the influence of fatty acids and other ligands on drug binding. The presented results reveal that the drug-binding properties of albumins cannot easily be predicted based only on a complex of albumin from another organism and the conservation of drug sites between species. This work shows that understanding organism-dependent differences is essential for assessing the suitability of particular albumins for structural or biochemical studies.
血清白蛋白是一种循环运输蛋白，在哺乳动物体内具有高度保守的序列和结构。其配体结合特性很重要，因为白蛋白调节许多药物的药代动力学。由于哺乳动物白蛋白之间结构保守程度高，常使用牛血清白蛋白等非人类白蛋白或动物模型来理解人类白蛋白与药物的相互作用。酮洛芬是一种常见的非甾体抗炎药，由白蛋白运输。在此研究中发现，尽管跨物种的结合位点具有保守性，但与其他哺乳动物白蛋白相比，酮洛芬与人血清白蛋白相互作用时表现出不同的结合位点偏好。研究了观察到的差异的原因，包括确定酮洛芬在特定位点的结合决定因素以及脂肪酸和其他配体对药物结合的影响。所呈现的结果表明，仅根据来自其他生物体的白蛋白复合物以及物种间药物位点的保守性，不容易预测白蛋白的药物结合特性。这项工作表明，了解生物体依赖性差异对于评估特定白蛋白用于结构或生化研究的适用性至关重要。
