Structural basis of the drug-binding specificity of human serum albumin
Structural basis of the drug-binding specificity of human serum albumin
复制标题
DOI：
10.1016/j.jmb.2005.07.075
复制
发表时间：
2005-10-14
影响因子：
5.6
通讯作者：
Curry, S
中科院分区：
文献类型：
--
作者：
Ghuman, J;Zunszain, PA;Curry, S
人血清白蛋白(HSA)是一种丰富的血浆蛋白，可与多种药物结合，从而限制其自由、有效的浓度。克服先导化合物与人血清白蛋白的结合亲和力的问题是药物开发中的一个重大挑战。对17种不同的HSA与各种药物和小分子毒素的复合体的结晶学分析揭示了蛋白质上两个主要药物结合位点的精确结构，确定了作为结合特异性的关键决定因素的残基，并阐明了两个口袋的灵活调节能力。分布在蛋白质上的药物的许多二级结合位点也已被确定。蛋白质的主要生理配体脂肪酸的结合被证明改变了药物位点1的极性和体积。这些结果阐明了积累的药物结合数据的解释，并为调节与HSA的相互作用的设计工作提供了有价值的模板。(C)2005爱思唯尔有限公司。保留所有权利。
Human serum albumin (HSA) is an abundant plasma protein that binds a remarkably wide range of drugs, thereby restricting their free, active concentrations. The problem of overcoming the binding affinity of lead compounds for HSA represents a major challenge in drug development. Crystallographic analysis of 17 different complexes of HSA with a wide variety of drugs and small-molecule toxins reveals the precise architecture of the two primary drug-binding sites on the protein, identifying residues that are key determinants of binding specificity and illuminating the capacity of both pockets for flexible accommodation. Numerous secondary binding sites for drugs distributed across the protein have also been identified. The binding of fatty acids, the primary physiological ligand for the protein, is shown to alter the polarity and increase the volume of drug site 1. These results clarify the interpretation of accumulated drug binding data and provide a valuable template for design efforts to modulate the interaction with HSA. (c) 2005 Elsevier Ltd. All rights reserved.