Mechanistic insight into the dynamics of Mur ligase through a comprehensive timescale-specific approach

Ogris, Iza (author), Zupančič, Barbara (author), Sosič, Izidor (author), Merzel, Franci (author), Golič Grdadolnik, Simona (author)

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 $^{15}$ 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.

• Language: English
• Keywords: ligases, solution-state NMR
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy; MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2025
• Number of pages: 15 str.
• Numbering: Vol. 8, [article no.] ǂ285
• PID: 20.500.12556/RUL-175861
• UDC: 615.4:54
• ISSN on article: 2399-3669
• DOI: 10.1038/s42004-025-01675-z
• COBISS.SI-ID: 250979587
• Publication date in RUL: 11.11.2025

Record is a part of a journal

• Title: Communications chemistry
• Shortened title: Commun. chem.
• Publisher: Macmillan Publishers, part of Springer Nature
• ISSN: 2399-3669
• COBISS.SI-ID: 529716505

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: muramil ligaze, sinteza bakterijskih peptidoglikanov, MurD ligaza, NMR v raztopini, farmacevtska kemija