Ogris Iza, Zupančič Barbara, Sosič Izidor, Merzel Franci, Grdadolnik Simona Golič
Laboratory for Molecular Structural Dynamics, Theory Department, National Institute of Chemistry, Ljubljana, Slovenia.
Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Commun Chem. 2025 Sep 29;8(1):285. doi: 10.1038/s42004-025-01675-z.
Muramyl ligases are multidomain enzymes involved in intracellular steps of bacterial peptidoglycan synthesis and are considered promising targets for the development of new antibacterial agents. Among them, Mur ligase D (MurD) has been most widely used for structure-based design, but success has been limited. Here, we determine the N NMR spin relaxation parameters of apo and bound states of MurD in solution. We introduce a principal component analysis of the spectral densities derived from the NMR relaxation data, which provides a mechanistic insight into the dynamic events at the residue level. Compensation effects (ps-ms timescale) and conformational exchange dynamics (µs-ms timescale), the latter also measured independently, were revealed in bound and unbound MurD, which should be considered in the design of structurally novel Mur inhibitors. The mechanistic consideration used in our study can be broadly applicable to other systems for deciphering their specific dynamic mechanisms.
胞壁酰连接酶是参与细菌肽聚糖合成细胞内步骤的多结构域酶，被认为是开发新型抗菌剂的有前景的靶点。其中，Mur连接酶D（MurD）在基于结构的设计中应用最为广泛，但成功案例有限。在此，我们测定了溶液中MurD的游离态和结合态的N NMR自旋弛豫参数。我们对源自NMR弛豫数据的光谱密度进行主成分分析，这为残基水平的动态事件提供了机理见解。在结合态和未结合态的MurD中均发现了补偿效应（皮秒-毫秒时间尺度）和构象交换动力学（微秒-毫秒时间尺度），后者也通过独立测量得到，在设计结构新颖的Mur抑制剂时应予以考虑。我们研究中使用的机理考量可广泛应用于其他系统，以解读其特定的动态机制。
