质子转运驱动 MmpL3 转运蛋白的变构构象变化
Proton transport drives allosteric conformational changes in the MmpL3 transporter
分子动力学模拟显示，耻垢分枝杆菌（Msmg）MmpL3 中保守 Asp-Tyr 二联体（Asp256-Tyr646 与 Asp645-Tyr257）的质子化状态决定其构象与底物结合口袋的开合。Asp256 质子化诱导二联体开放构象、提高局部水可及性，并使周质结合口袋趋于更开放的构型；Asp645 质子化则稳定闭合构象、降低水可及性并收窄跨膜结合口袋。结果支持一个顺序质子化模型：质子化依赖的构象变化与底物转运发生变构偶联。MmpL3 负责转运海藻糖单分枝菌酸酯（TMM）等细胞壁前体，是结核分枝杆菌（Mtb）的潜在治疗靶点。
来源：PLOS Computational Biology · journals.plos.org
by Lixinhao Yang, E. Jeffrey North, Helen I. Zgurskaya, Mary Jackson, James C. Gumbart
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health crisis, further complicated by increasing drug resistance. The mycobacterial membrane protein MmpL3, which is essential for transporting cell wall precursors such as trehalose monomycolate (TMM), is a promising therapeutic target. However, the mechanistic link between proton-driven dynamics and substrate transport in MmpL3 is not fully understood. In this study, we use molecular dynamics simulations to investigate how protonation of conserved Asp-Tyr dyads (Asp256-Tyr646 and Asp645-Tyr257) in Mycobacterium smegmatis (Msmg) MmpL3 regulates conformational changes and TMM binding. Protonation at Asp256 induces an open dyad conformation, increases local water accessibility, and is associated with a tendency toward more open configurations of the periplasmic binding pocket. In contrast, protonation at Asp645 stabilizes a closed dyad conformation, reduces water accessibility, and narrows the transmembrane binding pocket. These findings support a proposed sequential protonation model in which protonation-dependent conformational changes are allosterically coupled to substrate translocation.