Laboratory of Physiology and Genetics of Actinomycetes, Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, 2000, Argentina.
Plataforma Argentina de Biología Estructural y Metabolómica (PLABEM), Rosario, 2000, Argentina.
Nat Commun. 2020 Jul 24;11(1):3703. doi: 10.1038/s41467-020-17504-x.
Mycobacterium tuberculosis is a pathogen with a unique cell envelope including very long fatty acids, implicated in bacterial resistance and host immune modulation. FasR is a TetR-like transcriptional activator that plays a central role in sensing mycobacterial long-chain fatty acids and regulating lipid biosynthesis. Here we disclose crystal structures of M. tuberculosis FasR in complex with acyl effector ligands and with DNA, uncovering its molecular sensory and switching mechanisms. A long tunnel traverses the entire effector-binding domain, enabling long fatty acyl effectors to bind. Only when the tunnel is entirely occupied, the protein dimer adopts a rigid configuration with its DNA-binding domains in an open state, leading to DNA dissociation. The protein-folding hydrophobic core connects the two domains, and is completed into a continuous spine when the effector binds. Such a transmission spine is conserved in a large number of TetR-like regulators, offering insight into effector-triggered allosteric functional control.
结核分枝杆菌是一种病原体，其细胞包膜含有非常长的脂肪酸，这与细菌的耐药性和宿主免疫调节有关。FasR 是一种 TetR 样转录激活因子，在感知分枝杆菌长链脂肪酸和调节脂质生物合成方面发挥着核心作用。在这里，我们揭示了结核分枝杆菌 FasR 与酰基效应配体和 DNA 复合物的晶体结构，揭示了其分子感应和开关机制。一个长长的隧道贯穿整个效应物结合域，使长链脂肪酸效应物得以结合。只有当隧道完全被占据时，蛋白质二聚体才会采用刚性构象，其 DNA 结合域处于开放状态，导致 DNA 解离。蛋白质折叠的疏水性核心连接两个结构域，当效应物结合时，形成一个连续的脊柱。这种传递脊柱在大量的 TetR 样调节剂中是保守的，为效应物触发的变构功能控制提供了深入的了解。
