Zhang Yao, Lee Philbert, Liang Shichu, Zhou Zuping, Wu Xiaoyang, Yang Feng, Liang Hong
Key Laboratory of Ecology of Rare an Endangered Species and Environmental Protection, Ministry of Education of the People's Republic of China, Guangxi Normal University, Guilin, Guangxi, China.
Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA.
Chem Biol Drug Des. 2015 Nov;86(5):1178-84. doi: 10.1111/cbdd.12583. Epub 2015 May 28.
Human serum albumin (HSA) is the most abundant protein in plasma, which plays a central role in drug pharmacokinetics because most compounds bound to HSA in blood circulation. To understand binding characterization of non-steroidal anti-inflammatory drugs to HSA, we resolved the structure of diclofenac and HSA complex by X-ray crystallography. HSA-palmitic acid-diclofenac structure reveals two distinct binding sites for three diclofenac in HSA. One diclofenac is located at the IB subdomain, and its carboxylate group projects toward polar environment, forming hydrogen bond with one water molecule. The other two diclofenac molecules cobind in big hydrophobic cavity of the IIA subdomain without interactive association. Among them, one binds in main chamber of big hydrophobic cavity, and its carboxylate group forms hydrogen bonds with Lys199 and Arg218, as well as one water molecule, whereas another diclofenac binds in side chamber, its carboxylate group projects out cavity, forming hydrogen bond with Ser480.
人血清白蛋白（HSA）是血浆中含量最丰富的蛋白质，它在药物药代动力学中起着核心作用，因为大多数化合物在血液循环中与HSA结合。为了了解非甾体抗炎药与HSA的结合特性，我们通过X射线晶体学解析了双氯芬酸与HSA复合物的结构。HSA-棕榈酸-双氯芬酸结构揭示了HSA中三个双氯芬酸的两个不同结合位点。一个双氯芬酸位于IB亚结构域，其羧基朝向极性环境，与一个水分子形成氢键。另外两个双氯芬酸分子在IIA亚结构域的大疏水腔中共结合，没有相互作用关联。其中一个结合在大疏水腔的主腔中，其羧基与Lys199和Arg218以及一个水分子形成氢键，而另一个双氯芬酸结合在侧腔中，其羧基伸出腔外，与Ser480形成氢键。
