Mechanistic insight into the dynamics of Mur ligase through a comprehensive timescale-specific approach Article Swipe
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· 2025
· Open Access
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· DOI: https://doi.org/10.1038/s42004-025-01675-z
· OA: W4414602415
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 15 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.
