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Attenuating Listeria monocytogenes Virulence by Targeting the Regulatory Protein PrfA

James A D Good ; Christopher Andersson ; Sabine Hansen ; Jessica Wall ; K. Syam Krishnan ; Afshan Begum ; Christin Grundström ; Moritz S. Niemiec ; Karolis Vaitkevicius ; Erik Chorell ; Pernilla Wittung-Stafshede (Institutionen för biologi och bioteknik, Kemisk biologi) ; Uwe H. Sauer ; A. Elisabeth Sauer-Eriksson ; Fredrik Almqvist ; Jörgen Johansson
Cell Chemical Biology (24519456). Vol. 23 (2016), 3, p. 404-414.
[Artikel, refereegranskad vetenskaplig]

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.



Denna post skapades 2016-07-11.
CPL Pubid: 239230

 

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Institutioner (Chalmers)

Institutionen för biologi och bioteknik, Kemisk biologi

Ämnesområden

Biokemi och molekylärbiologi

Chalmers infrastruktur