Wu Yun-Jian, Zheng Qing-Chuan, Zhang Ji-Long, Chu Wen-Ting, Cui Ying-Lu, Wang Yan, Zhang Hong-Xing
State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun, 130023, Jilin, P R China.
J Mol Model. 2014 May;20(5):2236. doi: 10.1007/s00894-014-2236-2. Epub 2014 Apr 27.
Fosfomycin resistance kinases FomA, one of the key enzymes responsible for bacterial resistances to fosfomycin, has gained much attention recently due to the raising public concern for multi-drug resistant bacteria. Using molecular docking followed by molecular dynamics simulations, our group illustrated the process of fosfomycin induced conformational change of FomA. The detailed roles of the catalytic residues (Lys18, His58 and Thr210) during the formation of the enzyme-substrate complex were shown in our research. The organization functions of Gly53, Gly54, Ile61 and Leu75 were also highlighted. Furthermore, the cation-π interaction between Arg62 and Trp207 was observed and speculated to play an auxiliary role in the conformation change process of the enzyme. This detailed molecular level illustration of the formation of FomA·ATP·Mg·Fosfomycin complex could provide insight for both anti-biotic discovery and improvement of fosfomycin in the future.
磷霉素抗性激酶FomA是细菌对磷霉素产生抗性的关键酶之一，由于公众对多重耐药菌的关注度不断提高，它最近备受关注。通过分子对接和分子动力学模拟，我们团队阐明了磷霉素诱导FomA构象变化的过程。我们的研究展示了催化残基（Lys18、His58和Thr210）在酶-底物复合物形成过程中的详细作用。Gly53、Gly54、Ile61和Leu75的组织功能也得到了强调。此外，观察到Arg62和Trp207之间的阳离子-π相互作用，并推测其在酶的构象变化过程中起辅助作用。FomA·ATP·Mg·磷霉素复合物形成的这一详细分子水平阐释可为未来抗生素发现和磷霉素改进提供思路。
