6EXL
The Transcriptional Regulator PrfA from Listeria Monocytogenes in complex with a ring-fused 2-pyridone (MK206) - folded HTH motif
Summary for 6EXL
| Entry DOI | 10.2210/pdb6exl/pdb |
| Related | 5F1R |
| Descriptor | Listeriolysin positive regulatory factor A, [(3~{R})-3-carboxy-7-[(4-methylnaphthalen-1-yl)methyl]-5-oxidanylidene-2,3-dihydro-[1,3]thiazolo[3,2-a]pyridin-8-yl]-dimethyl-azanium, SODIUM ION, ... (5 entities in total) |
| Functional Keywords | transcription regulator, dna binding, 2-pyridone, drug design, listeria monocytogenes, dna binding protein |
| Biological source | Listeria monocytogenes |
| Total number of polymer chains | 2 |
| Total formula weight | 56047.43 |
| Authors | Hall, M.,Grundstrom, C.,Begum, A.,Kulen, M.,Lindgren, M.,Johansson, J.,Almqvist, F.,Sauer, U.H.,Sauer-Eriksson, A.E. (deposition date: 2017-11-08, release date: 2018-05-02, Last modification date: 2024-01-17) |
| Primary citation | Kulen, M.,Lindgren, M.,Hansen, S.,Cairns, A.G.,Grundstrom, C.,Begum, A.,van der Lingen, I.,Brannstrom, K.,Hall, M.,Sauer, U.H.,Johansson, J.,Sauer-Eriksson, A.E.,Almqvist, F. Structure-Based Design of Inhibitors Targeting PrfA, the Master Virulence Regulator of Listeria monocytogenes. J. Med. Chem., 61:4165-4175, 2018 Cited by PubMed Abstract: Listeria 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 (A), 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-A selective PrfA inhibitors with potent antivirulence properties. PubMed: 29667825DOI: 10.1021/acs.jmedchem.8b00289 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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