Attenuating Listeria monocytogenes Virulence by Targeting the Regulatory Protein PrfA
Artikel i vetenskaplig tidskrift, 2016
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.
Författare
James A D Good
Umeå universitet
Christopher Andersson
Umeå universitet
Sabine Hansen
Umeå universitet
Jessica Wall
Umeå universitet
K.S. Krishnan
Umeå universitet
Mannam Memorial NSS College
Afshan Begum
Umeå universitet
Christin Grundström
Umeå universitet
Moritz S. Niemiec
Umeå universitet
Karolis Vaitkevicius
Umeå universitet
E. Chorell
Umeå universitet
Pernilla Wittung Stafshede
Chalmers, Biologi och bioteknik, Kemisk biologi
Uwe H. Sauer
Umeå universitet
A. Elisabeth Sauer-Eriksson
Umeå universitet
F. Almqvist
Umeå universitet
Jörgen Johansson
Umeå universitet
Cell Chemical Biology
24519456 (ISSN) 24519448 (eISSN)
Vol. 23 3 404-414Ämneskategorier
Biokemi och molekylärbiologi
DOI
10.1016/j.chembiol.2016.02.013
PubMed
26991105