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Structural basis for the allosteric inhibition of UMP kinase from Gram‐positive bacteria, a promising antibacterial target
- Source :
- FEBS Journal, FEBS Journal, 2022, 289 (16), pp.4869-4887. ⟨10.1111/febs.16393⟩
- Publication Year :
- 2022
- Publisher :
- HAL CCSD, 2022.
-
Abstract
- International audience; Tuberculosis claims significantly more than one million lives each year. A feasible way to face the issue of drug resistance is the development of new antibiotics. Bacterial uridine 5’-monophosphate (UMP) kinase is a promis- ing target for novel antibiotic discovery as it is essential for bacterial sur- vival and has no counterpart in human cells. The UMP kinase from M. tuberculosis is also a model of particular interest for allosteric regula- tion with two effectors, GTP (positive) and UTP (negative). In this study, using X-ray crystallography and cryo-electron microscopy, we report for the first time a detailed description of the negative effector UTP-binding site of a typical Gram-positive behaving UMP kinase. Comparison between this snapshot of low affinity for Mg-ATP with our previous 3D-structure of the GTP-bound complex of high affinity for Mg-ATP led to a better understanding of the cooperative mechanism and the allosteric regulation of UMP kinase. Thermal shift assay and circular dichroism experiments corroborate our model of an inhibition by UTP linked to higher flexibility of the Mg-ATP-binding domain. These new structural insights provide valuable knowledge for future drug discovery strategies targeting bacterial UMP kinases.
- Subjects :
- crystal structure
allostery
[SDV]Life Sciences [q-bio]
Cryoelectron Microscopy
Uridine Triphosphate
Cell Biology
nucleotide metabolism
Gram-Positive Bacteria
Biochemistry
Anti-Bacterial Agents
Adenosine Triphosphate
effector
Allosteric Regulation
cryo-EM single particle analysis
Humans
Amino Acid Sequence
Guanosine Triphosphate
enzyme regulation
Nucleoside-Phosphate Kinase
Uridine Monophosphate
Molecular Biology
UMP kinase
Subjects
Details
- Language :
- English
- ISSN :
- 1742464X and 17424658
- Database :
- OpenAIRE
- Journal :
- FEBS Journal, FEBS Journal, 2022, 289 (16), pp.4869-4887. ⟨10.1111/febs.16393⟩
- Accession number :
- edsair.doi.dedup.....22742cddebdbe665ca6b9ce56c7745dd