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Structural and Functional Study of the Klebsiella pneumoniae VapBC Toxin-Antitoxin System, Including the Development of an Inhibitor That Activates VapC.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2020 Nov 25; Vol. 63 (22), pp. 13669-13679. Date of Electronic Publication: 2020 Nov 04. - Publication Year :
- 2020
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Abstract
- Klebsiella pneumoniae is one of the most critical opportunistic pathogens. TA systems are promising drug targets because they are related to the survival of bacterial pathogens. However, structural information on TA systems in K. pneumoniae remains lacking; therefore, it is necessary to explore this information for the development of antibacterial agents. Here, we present the first crystal structure of the VapBC complex from K. pneumoniae at a resolution of 2.00 Å. We determined the toxin inhibitory mechanism of the VapB antitoxin through an Mg <superscript>2+</superscript> switch, in which Mg <superscript>2+</superscript> is displaced by R79 of VapB. This inhibitory mechanism of the active site is a novel finding and the first to be identified in a bacterial TA system. Furthermore, inhibitors, including peptides and small molecules, that activate the VapC toxin were discovered and investigated. These inhibitors can act as antimicrobial agents by disrupting the VapBC complex and activating VapC. Our comprehensive investigation of the K. pneumoniae VapBC system will help elucidate an unsolved conundrum in VapBC systems and develop potential antimicrobial agents.
- Subjects :
- Amino Acid Sequence
Anti-Bacterial Agents chemistry
Bacterial Proteins antagonists & inhibitors
Bacterial Proteins drug effects
Bacterial Toxins antagonists & inhibitors
Crystallization
DNA-Binding Proteins drug effects
Drug Development methods
Klebsiella pneumoniae drug effects
Klebsiella pneumoniae genetics
Membrane Glycoproteins drug effects
Molecular Docking Simulation methods
Protein Structure, Secondary
Protein Structure, Tertiary
Toxin-Antitoxin Systems drug effects
Anti-Bacterial Agents pharmacology
Antitoxins chemistry
Antitoxins pharmacology
Bacterial Proteins chemistry
Bacterial Toxins chemistry
DNA-Binding Proteins chemistry
Klebsiella pneumoniae chemistry
Membrane Glycoproteins chemistry
Toxin-Antitoxin Systems physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 63
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33146528
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.0c01118