Bagley S C, Altman R B
Section on Medical Informatics, Stanford University, CA 94305-5479, USA.
Fold Des. 1996;1(5):371-9. doi: 10.1016/S1359-0278(96)00052-1.
Serine protease activity is critical for many biological processes and has arisen independently in a few different protein families. It is not clear, though, the degree to which these protease families share common biochemical and biophysical properties. We have used a computer program to study the properties that are shared by four serine protease active sites with no overall structural or sequence homology. The program systematically compares the region around the catalytic histidines from the four proteins with a set of noncatalytic histidines, used as controls. It reports the three-dimensional locations and level of statistical significance for those properties that distinguish the catalytic histidines from the noncatalytic ones. The method of analysis is general and can be applied easily to other active sites of interest.
As expected, some of the reported properties correspond to previously known features of the serine protease active site, including the catalytic triad and the oxyanion hole. Novel properties are also found, including the spatial distribution of charged, polar, and hydrophobic groups arranged to stabilize the catalytic residues, and a relative abundance of some residues (Val, Tyr, Leu, and Gly) around the active site.
Our findings show that in addition to some properties common to all the proteases examined, there are a set of preferred, but not required, properties that can be reliably observed only by aligning the sites and comparing them with carefully selected statistical controls.
丝氨酸蛋白酶活性对许多生物过程至关重要，并且在几个不同的蛋白质家族中独立出现。然而，目前尚不清楚这些蛋白酶家族在多大程度上具有共同的生化和生物物理特性。我们使用了一个计算机程序来研究四个没有整体结构或序列同源性的丝氨酸蛋白酶活性位点所共有的特性。该程序系统地将这四种蛋白质中催化组氨酸周围的区域与一组用作对照的非催化组氨酸进行比较。它报告了区分催化组氨酸和非催化组氨酸的那些特性的三维位置和统计显著性水平。分析方法具有通用性，可以轻松应用于其他感兴趣的活性位点。
正如预期的那样，一些报告的特性与丝氨酸蛋白酶活性位点先前已知的特征相对应，包括催化三联体和氧阴离子洞。还发现了一些新特性，包括为稳定催化残基而排列的带电、极性和疏水基团的空间分布，以及活性位点周围某些残基（缬氨酸、酪氨酸、亮氨酸和甘氨酸）的相对丰度。
我们的研究结果表明，除了所有检测的蛋白酶共有的一些特性外，还有一组优选但非必需的特性，只有通过比对这些位点并与精心挑选的统计对照进行比较才能可靠地观察到。
