Mattos C, Ringe D
Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02254, USA.
Nat Biotechnol. 1996 May;14(5):595-9. doi: 10.1038/nbt0596-595.
This review article begins with a discussion of fundamental differences between substrates and inhibitors, and some of the assumptions and goals underlying the design of a new ligand to a target protein. An overview is given of the methods currently used to locate and characterize ligand binding sites on protein surfaces, with focus on a novel approach: multiple solvent crystal structures (MSCS). In this method, the X-ray crystal structure of the target protein is solved in a variety of organic solvents. Each type of solvent molecule serves as a probe for complementary binding sites on the protein. The probe distribution on the protein surface allows the location of binding sites and the characterization of the potential ligand interactions within these sites. General aspects of the application of the MSCS method to porcine pancreatic elastase is discussed, and comparison of the results with those from X-ray crystal structures of elastase/inhibitor complexes is used to illustrate the potential of the method in aiding the process of rational drug design.
这篇综述文章首先讨论了底物与抑制剂之间的基本差异，以及针对目标蛋白设计新型配体所依据的一些假设和目标。概述了当前用于定位和表征蛋白质表面配体结合位点的方法，重点介绍了一种新方法：多溶剂晶体结构（MSCS）。在该方法中，目标蛋白的X射线晶体结构在多种有机溶剂中解析。每种类型的溶剂分子充当蛋白质上互补结合位点的探针。蛋白质表面上的探针分布可确定结合位点的位置，并表征这些位点内潜在的配体相互作用。讨论了MSCS方法应用于猪胰弹性蛋白酶的一般情况，并将结果与弹性蛋白酶/抑制剂复合物的X射线晶体结构结果进行比较，以说明该方法在辅助合理药物设计过程中的潜力。
