Glaser Fabian, Morris Richard J, Najmanovich Rafael J, Laskowski Roman A, Thornton Janet M
European Bioinformatics Institute, European Molecular Biology Laboratory, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
Proteins. 2006 Feb 1;62(2):479-88. doi: 10.1002/prot.20769.
The accurate identification of ligand binding sites in protein structures can be valuable in determining protein function. Once the binding site is known, it becomes easier to perform in silico and experimental procedures that may allow the ligand type and the protein function to be determined. For example, binding pocket shape analysis relies heavily on the correct localization of the ligand binding site. We have developed SURFNET-ConSurf, a modular, two-stage method for identifying the location and shape of potential ligand binding pockets in protein structures. In the first stage, the SURFNET program identifies clefts in the protein surface that are potential binding sites. In the second stage, these clefts are trimmed in size by cutting away regions distant from highly conserved residues, as defined by the ConSurf-HSSP database. The largest clefts that remain tend to be those where ligands bind. To test the approach, we analyzed a nonredundant set of 244 protein structures from the PDB and found that SURFNET-ConSurf identifies a ligand binding pocket in 75% of them. The trimming procedure reduces the original cleft volumes by 30% on average, while still encompassing an average 87% of the ligand volume. From the analysis of the results we conclude that for those cases in which the ligands are found in large, highly conserved clefts, the combined SURFNET-ConSurf method gives pockets that are a better match to the ligand shape and location. We also show that this approach works better for enzymes than for nonenzyme proteins.
准确识别蛋白质结构中的配体结合位点对于确定蛋白质功能具有重要价值。一旦确定了结合位点，进行计算机模拟和实验程序就会变得更加容易，这些程序可能有助于确定配体类型和蛋白质功能。例如，结合口袋形状分析在很大程度上依赖于配体结合位点的正确定位。我们开发了SURFNET-ConSurf，这是一种模块化的两阶段方法，用于识别蛋白质结构中潜在配体结合口袋的位置和形状。在第一阶段，SURFNET程序识别蛋白质表面可能作为结合位点的裂缝。在第二阶段，根据ConSurf-HSSP数据库的定义，通过切除远离高度保守残基的区域来缩小这些裂缝的大小。剩下的最大裂缝往往是配体结合的地方。为了测试该方法，我们分析了来自蛋白质数据银行（PDB）的一组244个非冗余蛋白质结构，发现SURFNET-ConSurf在其中75%的结构中识别出了配体结合口袋。修剪程序平均将原始裂缝体积减少了30%，同时仍然平均包含了87%的配体体积。通过对结果的分析，我们得出结论，对于那些配体存在于大的、高度保守的裂缝中的情况，SURFNET-ConSurf组合方法给出的口袋与配体形状和位置的匹配度更高。我们还表明，这种方法对酶的效果比对非酶蛋白质的效果更好。
