Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO, 80045, USA.
Mucosal and Vaccine Research Program Colorado, Division of Infectious Disease, University of Colorado Denver School of Medicine and Denver Veterans Affairs Medical Center, Aurora, CO, 80045, USA.
Nat Commun. 2020 Nov 27;11(1):6063. doi: 10.1038/s41467-020-19887-3.
Opportunistic pathogens such as Streptococcus pneumoniae secrete a giant metalloprotease virulence factor responsible for cleaving host IgA1, yet the molecular mechanism has remained unknown since their discovery nearly 30 years ago despite the potential for developing vaccines that target these enzymes to block infection. Here we show through a series of cryo-electron microscopy single particle reconstructions how the Streptococcus pneumoniae IgA1 protease facilitates IgA1 substrate recognition and how this can be inhibited. Specifically, the Streptococcus pneumoniae IgA1 protease subscribes to an active-site-gated mechanism where a domain undergoes a 10.0 Å movement to facilitate cleavage. Monoclonal antibody binding inhibits this conformational change, providing a direct means to block infection at the host interface. These structural studies explain decades of biological and biochemical studies and provides a general strategy to block Streptococcus pneumoniae IgA1 protease activity to potentially prevent infection.
机会性病原体,如肺炎链球菌,会分泌一种巨型金属蛋白酶毒力因子,负责切割宿主 IgA1,尽管有开发针对这些酶的疫苗以阻断感染的潜力,但自近 30 年前发现以来,其分子机制仍不清楚。在这里,我们通过一系列冷冻电子显微镜单颗粒重建展示了肺炎链球菌 IgA1 蛋白酶如何促进 IgA1 底物的识别,以及如何抑制这种识别。具体来说,肺炎链球菌 IgA1 蛋白酶采用活性位点门控机制,其中一个结构域发生 10.0 Å 的运动以促进切割。单克隆抗体结合抑制这种构象变化,为在宿主界面阻断感染提供了一种直接手段。这些结构研究解释了几十年来的生物学和生物化学研究,并提供了一种阻止肺炎链球菌 IgA1 蛋白酶活性的通用策略,以潜在预防感染。