Singh Rajendra Kumar, Ethayathulla A S, Jabeen Talat, Sharma Sujata, Kaur Punit, Singh Tej P
Department of Biophysics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029, India.
J Drug Target. 2005 Feb;13(2):113-9. doi: 10.1080/10611860400024078.
Phospholipase A2 is potentially an important target for structure-based rational drug design. In order to determine the involvement of phospholipase A2 in the action of non-steroidal anti-inflammatory drugs (NSAIDs), the crystal structure of the complex formed between phospholipase A2 and aspirin has been determined at 1.9 angstroms resolution. The structure contains 915 protein atoms, 1 calcium ion, 13 atoms of aspirin and 105 water molecules. The observed electron density of the aspirin molecule in the structure was of very high quality thus allowing the precise determination of its atomic coordinates leading to the clear description of its interactions with the enzyme. The structure of the complex clearly shows that aspirin is literally embedded in the hydrophobic environment of PLA2. It is so placed in the substrate binding channel that it forms several important attractive interactions with calcium ion, His 48 and Asp 49. Thus, the structure of the complex clearly shows that aspirin occupies a favourable place in the specific binding site of PLA2. The binding studies have shown that acetyl salicylate (aspirin) binds to PLA2 enzyme specifically with a dissociation constant of 6.4 x 10(-6) M. The structural details and binding data suggest that the inhibition of PLA2 by aspirin is of pharmacological
磷脂酶A2可能是基于结构的合理药物设计的重要靶点。为了确定磷脂酶A2在非甾体抗炎药（NSAIDs）作用中的参与情况，已在1.9埃分辨率下测定了磷脂酶A2与阿司匹林形成的复合物的晶体结构。该结构包含915个蛋白质原子、1个钙离子、13个阿司匹林原子和105个水分子。结构中阿司匹林分子的观测电子密度质量非常高，因此能够精确确定其原子坐标，从而清晰描述其与酶的相互作用。复合物的结构清楚地表明，阿司匹林实际上嵌入在磷脂酶A2的疏水环境中。它位于底物结合通道中，与钙离子、组氨酸48和天冬氨酸49形成了几种重要的吸引相互作用。因此，复合物的结构清楚地表明，阿司匹林在磷脂酶A2的特异性结合位点占据了一个有利位置。结合研究表明，乙酰水杨酸（阿司匹林）以6.4×10⁻⁶ M的解离常数特异性结合到磷脂酶A2酶上。结构细节和结合数据表明，阿司匹林对磷脂酶A2的抑制具有药理学性质
