Department of Chemical Science and Technology University of Rome Tor Vergata, Italy.
Virology. 2010 Sep 30;405(2):424-38. doi: 10.1016/j.virol.2010.05.035. Epub 2010 Jul 13.
The first structural characterization of the genotype 3a Hepatitis C Virus NS3 protease is reported, providing insight into the differential susceptibility of 1b and 3a proteases to certain inhibitors. Interaction of the 3a NS3 protease with a P2-P4 macrocyclic and a linear phenethylamide inhibitor was investigated. In addition, the effect of the NS4A cofactor binding on the conformation of the protease was analyzed. Complexation of NS3 with the phenethylamide inhibitor significantly stabilizes the protease but binding does not involve residues 168 and 123, two key amino acids underlying the different inhibition of genotype 1b vs. 3a proteases by P2-P4 macrocycles. Therefore, we studied the dynamic behavior of these two residues in the phenethylamide complex, serving as a model of the situation in the apo 3a protein, in order to explore the structural basis of the inhibition potency shift between the proteases of the genotypes 1b and 3a.
首次对基因型 3a 丙型肝炎病毒 NS3 蛋白酶进行结构特征分析，深入了解 1b 和 3a 蛋白酶对某些抑制剂的不同敏感性。研究了 3a NS3 蛋白酶与 P2-P4 大环和线性苯乙酰胺抑制剂的相互作用。此外，还分析了 NS4A 辅助因子结合对蛋白酶构象的影响。NS3 与苯乙酰胺抑制剂的络合显著稳定了蛋白酶，但结合不涉及两个关键氨基酸残基 168 和 123，这两个氨基酸残基是 P2-P4 大环对基因型 1b 和 3a 蛋白酶抑制作用不同的基础。因此，我们研究了这两个残基在苯乙酰胺复合物中的动态行为，作为 apo 3a 蛋白中情况的模型，以探索基因型 1b 和 3a 蛋白酶之间抑制效力转移的结构基础。
