6ev0
The Transcriptional Regulator PrfA from Listeria Monocytogenes in complex with a ring-fused 2-pyridone (AC129)The Transcriptional Regulator PrfA from Listeria Monocytogenes in complex with a ring-fused 2-pyridone (AC129)
Structural highlights
Function[PRFA_LISMO] Positively regulates expression of listeriolysin, of 1-phosphadidylinositol phosphodiesterase (PI-PLC) and other virulence factors. Publication Abstract from PubMedListeria monocytogenes is a bacterial pathogen that controls much of its virulence through the transcriptional regulator PrfA. In this study, we describe structure-guided design and synthesis of a set of PrfA inhibitors based on ring-fused 2-pyridone heterocycles. Our most effective compound decreased virulence factor expression, reduced bacterial uptake into eukaryotic cells, and improved survival of chicken embryos infected with L. monocytogenes compared to previously identified compounds. Crystal structures identified an intraprotein "tunnel" as the main inhibitor binding site (AI), where the compounds participate in an extensive hydrophobic network that restricts the protein's ability to form functional DNA-binding helix-turn-helix (HTH) motifs. Our studies also revealed a hitherto unsuspected structural plasticity of the HTH motif. In conclusion, we have designed 2-pyridone analogues that function as site-AI selective PrfA inhibitors with potent antivirulence properties. Structure-Based Design of Inhibitors Targeting PrfA, the Master Virulence Regulator of Listeria monocytogenes.,Kulen M, Lindgren M, Hansen S, Cairns AG, Grundstrom C, Begum A, van der Lingen I, Brannstrom K, Hall M, Sauer UH, Johansson J, Sauer-Eriksson AE, Almqvist F J Med Chem. 2018 Apr 27. doi: 10.1021/acs.jmedchem.8b00289. PMID:29667825[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||||||