Attenuating Listeria monocytogenes Virulence by Targeting the Regulatory Protein PrfA.Show others and affiliations
2016 (English)In: Cell chemical biology, ISSN 2451-9456, Vol. 23, no 3, p. 404-14, article id S2451-9456(16)30049-6Article in journal (Refereed) Published
Abstract [en]
The transcriptional activator PrfA, a member of the Crp/Fnr family, controls the expression of some key virulence factors necessary for infection by the human bacterial pathogen Listeria monocytogenes. Phenotypic screening identified ring-fused 2-pyridone molecules that at low micromolar concentrations attenuate L. monocytogenes cellular uptake by reducing the expression of virulence genes. These inhibitors bind the transcriptional regulator PrfA and decrease its affinity for the consensus DNA-binding site. Structural characterization of this interaction revealed that one of the ring-fused 2-pyridones, compound 1, binds at two separate sites on the protein: one within a hydrophobic pocket or tunnel, located between the C- and N-terminal domains of PrfA, and the second in the vicinity of the DNA-binding helix-turn-helix motif. At both sites the compound interacts with residues important for PrfA activation and helix-turn-helix formation. Ring-fused 2-pyridones represent a new class of chemical probes for studying virulence in L. monocytogenes.
Place, publisher, year, edition, pages
2016. Vol. 23, no 3, p. 404-14, article id S2451-9456(16)30049-6
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-129464DOI: 10.1016/j.chembiol.2016.02.013PubMedID: 26991105OAI: oai:DiVA.org:umu-129464DiVA, id: diva2:369
Note
753
2017-04-102017-04-102019-01-15Bibliographically approved
In thesis