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Data de publicació

2026-02-04

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cc-by-nc-nd (c) Pedraz López, Lucas et al., 2026
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/228510

Structure and mechanistic basis of NrdR, a bacterial master regulator of ribonucleotide reduction

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Recurs relacionat

https://doi.org/10.1016/j.ijbiomac.2026.150647

Resum

Ribonucleotide reductases (RNRs) are the essential enzymes responsible for synthesizing dNTPs, the building blocks of DNA. In bacteria, the entire RNR network is controlled by the master regulator NrdR. As a regulator of an essential pathway with no eukaryotic equivalent, NrdR is a promising antimicrobial target. Recent structural studies have outlined a mechanism of action for NrdR, in which ATP and dATP induce changes in the protein quaternary structure, regulating RNR repression. However, due to a lack of functional studies linking the known structures to their biological roles, the activation mechanism of NrdR is not yet fully understood. Here, we conducted a comprehensive study of NrdR in Escherichia coli and Pseudomonas aeruginosa. We delimited the NrdR regulon, combining transcriptomics and motif-based sequence analysis. We crystallized E. coli NrdR and identified the protein-protein interfaces involved in its oligomerization, including strong interactions between NrdR dimers to form tetramers, and less stable interfaces connecting such tetramers. We examined the variability of the quaternary structures of NrdR depending on the bound nucleotides by SEC-MALS and atomic force microscopy, and correlated structure to function using point mutations, EMSAs, and in vitro transcription assays. Overall, our results demonstrate the mechanism used by NrdR to modulate its quaternary structure and activity, deciphering essential interactions between subunits, and paving the way for targeted antimicrobial therapies.

Matèries

Dihidrofolat reductasa, Síntesi de l'ADN, Regulació genètica

Matèries (anglès)

Tetrahydrofolate dehydrogenase, DNA synthesis, Genetic regulation

Citació

Col·leccions

Articles publicats en revistes (Enginyeria Electrònica i Biomèdica)
Articles publicats en revistes (Genètica, Microbiologia i Estadística)
Articles publicats en revistes (Institut de Bioenginyeria de Catalunya (IBEC))

Citació

PEDRAZ LÓPEZ, Lucas, et al. Structure and mechanistic basis of NrdR, a bacterial master regulator of ribonucleotide reduction. International Journal of Biological Macromolecules. 2026. ISSN 0141-8130. [consulta: 8 de maig de 2026]. Disponible a: https://hdl.handle.net/2445/228510

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