Sessions R B, Dauber-Osguthorpe P, Campbell M M, Osguthorpe D J
Molecular Graphics Unit, University of Bath, United Kingdom.
Proteins. 1992 Sep;14(1):45-64. doi: 10.1002/prot.340140107.
Molecular graphics and molecular mechanics techniques have been used to study the mode of ligand binding and mechanism of action of the enzyme phospholipase A2. A substrate-enzyme complex was constructed based on the crystal structure of the apoenzyme. The complex was minimized to relieve initial strain, and the structural and energetic features of the resultant complex analyzed in detail, at the molecular and residue level. The minimized complex was then used as a basis for examining the action of the enzyme on modified substrates, binding of inhibitors to the enzyme, and possible reaction intermediate complexes. The model is compatible with the suggested mechanism of hydrolysis and with experimental data about stereoselectivity, efficiency of hydrolysis of modified substrates, and inhibitor potency. In conclusion, the model can be used as a tool in evaluating new ligands as possible substrates and in the rational design of inhibitors, for the therapeutic treatment of diseases such as rheumatoid arthritis, atherosclerosis, and asthma.
分子图形学和分子力学技术已被用于研究磷脂酶A2的配体结合模式和作用机制。基于脱辅基酶的晶体结构构建了底物-酶复合物。对该复合物进行了能量最小化以缓解初始应变，并在分子和残基水平上详细分析了所得复合物的结构和能量特征。然后将能量最小化的复合物用作研究该酶对修饰底物的作用、抑制剂与酶的结合以及可能的反应中间体复合物的基础。该模型与提出的水解机制以及关于立体选择性、修饰底物的水解效率和抑制剂效力的实验数据相兼容。总之，该模型可作为一种工具，用于评估新的配体作为可能的底物，并用于合理设计抑制剂，以治疗类风湿性关节炎、动脉粥样硬化和哮喘等疾病。
