Abstract：
S-Adenosyl-l-homocysteine hydrolase (SAHH) is a crucial enzyme that governs S-adenosyl methionine (SAM)-dependent methylation reactions within cells and regulates the intracellular concentration of SAH. Legionella pneumophila, the causative pathogen of Legionnaires\' disease, encodes Lpg2021, which is the first identified dimeric SAHH in bacteria and is a promising target for drug development. Here, we report the structure of Lpg2021 in its ligand-free state and in complexes with adenine (ADE), adenosine (ADO), and 3-Deazaneplanocin A (DZNep). X-ray crystallography, isothermal titration calorimetry (ITC), and molecular docking were used to elucidate the binding mechanisms of Lpg2021 to its substrates and inhibitors. Virtual screening was performed to identify potential Lpg2021 inhibitors. This study contributes a novel perspective to the understanding of SAHH evolution and establishes a structural framework for designing specific inhibitors targeting pathogenic Legionella pneumophila SAHH.
摘要：
S-腺苷-1-高半胱氨酸水解酶（SAHH）是一种关键酶，可控制细胞内S-腺苷甲硫氨酸（SAM）依赖性甲基化反应并调节SAH的细胞内浓度。嗜肺军团菌,军团病的病原体，编码Lpg2021，这是第一个在细菌中发现的二聚体SAHH，是药物开发的有希望的靶标。这里,我们报告了LPG2021在其无配体状态和与腺嘌呤（ADE）的复合物中的结构，腺苷（ADO），和3-DeazanplanocinA（DZNep）。X射线晶体学,等温滴定量热法(ITC)，和分子对接用于阐明Lpg2021与其底物和抑制剂的结合机制。进行虚拟筛选以鉴定潜在的Lpg2021抑制剂。这项研究为理解SAHH的进化提供了新的视角，并为设计针对致病性嗜肺军团菌SAHH的特异性抑制剂建立了结构框架。
