Center for Advanced Biotechnology and Medicine and Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854, USA.
Proc Natl Acad Sci U S A. 2013 May 21;110(21):8525-30. doi: 10.1073/pnas.1302819110. Epub 2013 May 6.
Staphylococcus aureus VraR, a vancomycin-resistance-associated response regulator, activates a cell-wall-stress stimulon in response to antibiotics that inhibit cell wall formation. X-ray crystal structures of VraR in both unphosphorylated and beryllofluoride-activated states have been determined, revealing a mechanism of phosphorylation-induced dimerization that features a deep hydrophobic pocket at the center of the receiver domain interface. Unphosphorylated VraR exists in a closed conformation that inhibits dimer formation. Phosphorylation at the active site promotes conformational changes that are propagated throughout the receiver domain, promoting the opening of a hydrophobic pocket that is essential for homodimer formation and enhanced DNA-binding activity. This prominent feature in the VraR dimer can potentially be exploited for the development of novel therapeutics to counteract antibiotic resistance in this important pathogen.
金黄色葡萄球菌 VraR 是一种与万古霉素耐药相关的反应调节因子，可在抗生素抑制细胞壁形成时激活细胞壁应激刺激物。已确定了 VraR 在未磷酸化和铍激活状态下的 X 射线晶体结构，揭示了一种磷酸化诱导二聚化的机制，该机制在受体结构域界面的中心具有一个深的疏水性口袋。未磷酸化的 VraR 处于抑制二聚化的封闭构象。活性位点的磷酸化促进构象变化，这种变化在整个受体结构域中传播，促进疏水性口袋的打开，这对于同源二聚体形成和增强 DNA 结合活性是必需的。VraR 二聚体中的这一显著特征可能被用于开发新型治疗方法，以对抗这种重要病原体的抗生素耐药性。
