Rotonda J, Garcia-Calvo M, Bull H G, Geissler W M, McKeever B M, Willoughby C A, Thornberry N A, Becker J W
Department of Endocrinology and Chemical Biology, Merck Research Laboratories, Rahway, NJ 07065-0900, USA.
Chem Biol. 2001 Apr;8(4):357-68. doi: 10.1016/s1074-5521(01)00018-7.
Granzyme B, one of the most abundant granzymes in cytotoxic T-lymphocyte (CTL) granules, and members of the caspase (cysteine aspartyl proteinases) family have a unique cleavage specificity for aspartic acid in P1 and play critical roles in the biochemical events that culminate in cell death.
We have determined the three-dimensional structure of the complex of the human granzyme B with a potent tetrapeptide aldehyde inhibitor. The Asp-specific S1 subsite of human granzyme B is significantly larger and less charged than the corresponding Asp-specific site in the apoptosis-promoting caspases, and also larger than the corresponding subsite in rat granzyme B.
The above differences account for the variation in substrate specificity among granzyme B, other serine proteases and the caspases, and enable the design of specific inhibitors that can probe the physiological functions of these proteins and the disease states with which they are associated.
颗粒酶B是细胞毒性T淋巴细胞（CTL）颗粒中含量最丰富的颗粒酶之一，半胱天冬酶（半胱氨酸天冬氨酸蛋白酶）家族成员对P1位的天冬氨酸具有独特的切割特异性，并在最终导致细胞死亡的生化事件中起关键作用。
我们确定了人颗粒酶B与一种有效的四肽醛抑制剂复合物的三维结构。人颗粒酶B的天冬氨酸特异性S1亚位点比促凋亡半胱天冬酶中相应的天冬氨酸特异性位点大得多且电荷少，也比大鼠颗粒酶B中的相应亚位点大。
上述差异解释了颗粒酶B、其他丝氨酸蛋白酶和半胱天冬酶之间底物特异性的变化，并有助于设计能够探究这些蛋白质的生理功能及其相关疾病状态的特异性抑制剂。
