Tong L, Qian C, Massariol M J, Bonneau P R, Cordingley M G, Lagacé L
Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut 06877, USA.
Nature. 1996 Sep 19;383(6597):272-5. doi: 10.1038/383272a0.
Human cytomegalovirus (hCMV), a herpesvirus, infects up to 70% of the general population in the United States and can cause morbidity and mortality in immunosuppressed individuals (organ-transplant recipients and AIDS patients) and congenitally infected newborns. hCMV protease is essential for the production of mature infectious virions, as it performs proteolytic processing near the carboxy terminus (M-site) of the viral assembly protein precursor. hCMV protease is a serine protease, although it has little homology to other clans of serine proteases. Here we report the crystal structure of hCMV protease at 2.0 angstroms resolution, and show that it possesses a new polypeptide backbone fold. Ser 132 and His 63 are found in close proximity in the active site, confirming earlier biochemical and mutagenesis studies. The structure suggests that the third member of the triad is probably His 157. A dimer of the protease with an extensive interface is found in the crystal structure. This structure information will help in the design and optimization of inhibitors against herpesvirus proteases.
人巨细胞病毒（hCMV）是一种疱疹病毒，在美国高达70%的普通人群中存在感染情况，并且可在免疫抑制个体（器官移植受者和艾滋病患者）以及先天性感染的新生儿中导致发病和死亡。hCMV蛋白酶对于成熟感染性病毒粒子的产生至关重要，因为它在病毒装配蛋白前体的羧基末端（M位点）附近进行蛋白水解加工。hCMV蛋白酶是一种丝氨酸蛋白酶，尽管它与其他丝氨酸蛋白酶家族的同源性很低。在此我们报道了hCMV蛋白酶在2.0埃分辨率下的晶体结构，并表明它具有一种新的多肽主链折叠。在活性位点中发现丝氨酸132和组氨酸63靠得很近，这证实了早期的生化和诱变研究。该结构表明三联体的第三个成员可能是组氨酸157。在晶体结构中发现了具有广泛界面的蛋白酶二聚体。这一结构信息将有助于设计和优化针对疱疹病毒蛋白酶的抑制剂。
