Wagner Jonathan M, Zadrozny Kaneil K, Chrustowicz Jakub, Purdy Michael D, Yeager Mark, Ganser-Pornillos Barbie K, Pornillos Owen
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States.
Department of Medicine, Division of Cardiovascular Medicine, University of Virginia Health System, Charlottesville, United States.
Elife. 2016 Jul 14;5:e17063. doi: 10.7554/eLife.17063.
Virus assembly and maturation proceed through the programmed operation of molecular switches, which trigger both local and global structural rearrangements to produce infectious particles. HIV-1 contains an assembly and maturation switch that spans the C-terminal domain (CTD) of the capsid (CA) region and the first spacer peptide (SP1) of the precursor structural protein, Gag. The crystal structure of the CTD-SP1 Gag fragment is a goblet-shaped hexamer in which the cup comprises the CTD and an ensuing type II β-turn, and the stem comprises a 6-helix bundle. The β-turn is critical for immature virus assembly and the 6-helix bundle regulates proteolysis during maturation. This bipartite character explains why the SP1 spacer is a critical element of HIV-1 Gag but is not a universal property of retroviruses. Our results also indicate that HIV-1 maturation inhibitors suppress unfolding of the CA-SP1 junction and thereby delay access of the viral protease to its substrate.
病毒组装和成熟通过分子开关的程序性操作进行，这些分子开关触发局部和整体的结构重排以产生感染性颗粒。HIV-1包含一个组装和成熟开关，它跨越衣壳（CA）区域的C末端结构域（CTD）和前体结构蛋白Gag的第一个间隔肽（SP1）。CTD-SP1 Gag片段的晶体结构是一个杯状六聚体，其中杯状部分由CTD和随后的II型β-转角组成，而茎部由一个6螺旋束组成。β-转角对于未成熟病毒组装至关重要，而6螺旋束在成熟过程中调节蛋白水解。这种二分特性解释了为什么SP1间隔区是HIV-1 Gag的关键元件，但不是逆转录病毒的普遍特性。我们的结果还表明，HIV-1成熟抑制剂抑制CA-SP1连接处的解折叠，从而延迟病毒蛋白酶接近其底物。
