The Protein Crystallography Unit, ARC Centre of Excellence in Structural and Functional Microbial Genomics, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.
Structure. 2010 Feb 10;18(2):228-38. doi: 10.1016/j.str.2009.11.014.
Many pathogenic bacteria have sophisticated mechanisms to interfere with the mammalian immune response. These include the disruption of host extracellular ATP levels that, in humans, is tightly regulated by the nucleoside triphosphate diphosphohydrolase family (NTPDases). NTPDases are found almost exclusively in eukaryotes, the notable exception being their presence in some pathogenic prokaryotes. To address the function of bacterial NTPDases, we describe the structures of an NTPDase from the pathogen Legionella pneumophila (Lpg1905/Lp1NTPDase) in its apo state and in complex with the ATP analog AMPPNP and the subtype-specific NTPDase inhibitor ARL 67156. Lp1NTPDase is structurally and catalytically related to eukaryotic NTPDases and the structure provides a basis for NTPDase-specific inhibition. Furthermore, we demonstrate that the activity of Lp1NTPDase correlates directly with intracellular replication of Legionella within macrophages. Collectively, these findings provide insight into the mechanism of this enzyme and highlight its role in host-pathogen interactions.
许多病原菌具有复杂的机制来干扰哺乳动物的免疫反应。这些机制包括破坏宿主细胞外 ATP 水平，而在人类中，细胞外 ATP 水平由核苷三磷酸二磷酸水解酶家族（NTPDases）严格调控。NTPDases 几乎只存在于真核生物中，一个显著的例外是它们存在于一些病原性原核生物中。为了研究细菌 NTPDases 的功能，我们描述了病原体嗜肺军团菌（Legionella pneumophila）中 NTPDase（Lpg1905/Lp1NTPDase）的结构，分别为其在无配体状态和与 ATP 类似物 AMPPNP 以及亚型特异性 NTPDase 抑制剂 ARL 67156 形成复合物的状态。Lp1NTPDase 在结构和催化上与真核 NTPDases 相关，该结构为 NTPDase 特异性抑制提供了基础。此外，我们证明 Lp1NTPDase 的活性与军团菌在巨噬细胞内的复制直接相关。总的来说，这些发现提供了对该酶作用机制的深入了解，并强调了其在宿主-病原体相互作用中的作用。
