Petitpas I, Bhattacharya A A, Twine S, East M, Curry S
Biophysics Section, Blackett Laboratory, Imperial College of Science, Technology, and Medicine, London SW7 2BW, United Kingdom.
J Biol Chem. 2001 Jun 22;276(25):22804-9. doi: 10.1074/jbc.M100575200. Epub 2001 Apr 2.
Human serum albumin (HSA) is an abundant transport protein found in plasma that binds a wide variety of drugs in two primary binding sites (I and II) and can have a significant impact on their pharmacokinetics. We have determined the crystal structures at 2.5 A-resolution of HSA-myristate complexed with the R-(+) and S-(-) enantiomers of warfarin, a widely used anticoagulant that binds to the protein with high affinity. The structures confirm that warfarin binds to drug site I (in subdomain IIA) in the presence of fatty acids and reveal the molecular details of the protein-drug interaction. The two enantiomers of warfarin adopt very similar conformations when bound to the protein and make many of the same specific contacts with amino acid side chains at the binding site, thus accounting for the relative lack of stereospecificity of the HSA-warfarin interaction. The conformation of the warfarin binding pocket is significantly altered upon binding of fatty acids, and this can explain the observed enhancement of warfarin binding to HSA at low levels of fatty acid.
人血清白蛋白（HSA）是血浆中一种丰富的转运蛋白，它在两个主要结合位点（I和II）结合多种药物，并对其药代动力学有重大影响。我们已经确定了HSA-肉豆蔻酸与华法林的R-(+)和S-(-)对映体复合的2.5埃分辨率晶体结构，华法林是一种广泛使用的抗凝剂，与该蛋白具有高亲和力。这些结构证实，在脂肪酸存在的情况下，华法林与药物位点I（在亚结构域IIA中）结合，并揭示了蛋白质-药物相互作用的分子细节。华法林的两种对映体与蛋白质结合时采用非常相似的构象，并在结合位点与氨基酸侧链进行许多相同的特异性接触，因此解释了HSA-华法林相互作用相对缺乏立体特异性的原因。脂肪酸结合后，华法林结合口袋的构象发生显著改变，这可以解释在低水平脂肪酸情况下观察到的华法林与HSA结合增强的现象。
