6EXL

The Transcriptional Regulator PrfA from Listeria Monocytogenes in complex with a ring-fused 2-pyridone (MK206) - folded HTH motif

6EXL の概要

• エントリーDOI: 10.2210/pdb6exl/pdb
• 関連するPDBエントリー: 5F1R
• 分子名称: 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)
• 機能のキーワード: transcription regulator, dna binding, 2-pyridone, drug design, listeria monocytogenes, dna binding protein
• 由来する生物種: Listeria monocytogenes
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 56047.43

構造登録者

Hall, M.,Grundstrom, C.,Begum, A.,Kulen, M.,Lindgren, M.,Johansson, J.,Almqvist, F.,Sauer, U.H.,Sauer-Eriksson, A.E. (登録日: 2017-11-08, 公開日: 2018-05-02, 最終更新日: 2024-01-17)

主引用文献

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

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: 29667825
DOI: 10.1021/acs.jmedchem.8b00289

実験手法

X-RAY DIFFRACTION (1.9 Å)