Miller M, Jaskólski M, Rao J K, Leis J, Wlodawer A
Crystallography Laboratory, NCI-Frederick Cancer Research Facility, Maryland 21701.
Nature. 1989 Feb 9;337(6207):576-9. doi: 10.1038/337576a0.
Retroviral gag, pol and env gene products are translated as precursor polyproteins, which are cleaved by virus-encoded proteases to produce the mature proteins found in virions. On the basis of the conserved Asp-Thr/Ser-Gly sequence at the putative protease active sites, and other biochemical evidence, retroviral proteases have been predicted to be in the family of pepsin-like aspartic proteases. It has been suggested that aspartic proteases evolved from a smaller, dimeric ancestral protein, and a recent model of the human immunodeficiency virus (HIV) protease postulated that a symmetric dimer of this enzyme is equivalent to a pepsin-like aspartic protease. We have now determined the crystal structure of Rous sarcoma virus (RSV) protease at 3-A resolution and find it is dimeric and has a structure similar to aspartic proteases. This structure should provide a useful basis for the modelling of the structures of other retroviral proteases, such as that of HIV, and also for the rational design of protease inhibitors as potential antiviral drugs.
逆转录病毒的gag、pol和env基因产物作为前体多蛋白被翻译出来，这些前体多蛋白被病毒编码的蛋白酶切割，以产生在病毒粒子中发现的成熟蛋白。基于假定的蛋白酶活性位点处保守的天冬氨酸-苏氨酸/丝氨酸-甘氨酸序列以及其他生化证据，逆转录病毒蛋白酶被预测属于胃蛋白酶样天冬氨酸蛋白酶家族。有人提出天冬氨酸蛋白酶由一种较小的二聚体祖先蛋白进化而来，并且最近关于人类免疫缺陷病毒（HIV）蛋白酶的一个模型假定该酶的对称二聚体等同于一种胃蛋白酶样天冬氨酸蛋白酶。我们现已确定劳斯肉瘤病毒（RSV）蛋白酶的晶体结构，分辨率为3埃，发现它是二聚体，并且具有与天冬氨酸蛋白酶相似的结构。该结构应为其他逆转录病毒蛋白酶（如HIV蛋白酶）的结构建模以及作为潜在抗病毒药物的蛋白酶抑制剂的合理设计提供有用的基础。
