PDBsum entry 6ev0

DNA binding protein

PDB id: 6ev0

Contents

Protein chains

230 a.a.

Ligands

BYK ×2

IPA ×2

C8N

Waters ×44

PDB id:

6ev0

Name:

DNA binding protein

Title:

The transcriptional regulator prfa from listeria monocytogenes in complex with a ring-fused 2-pyridone (ac129)

Structure:

Listeriolysin regulatory protein. Chain: a, b. Engineered: yes

Source:

Listeria monocytogenes egd-e. Organism_taxid: 169963. Strain: atcc baa-679 / egd-e. Gene: prfa, lmo0200. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.30Å R-factor: 0.215 R-free: 0.263

Authors:

A.Begum,M.Hall,C.Grundstrom,A.G.Cairns,M.Kulen,M.Lindgren, J.Johansson,F.Almqvist,U.H.Sauer,A.E.Sauer-Eriksson

Key ref:

M.Kulén et al. (2018). Structure-Based Design of Inhibitors Targeting PrfA, the Master Virulence Regulator of Listeria monocytogenes. J Med Chem, 61, 4165-4175. PubMed id: 29667825 DOI: 10.1021/acs.jmedchem.8b00289

Date:

31-Oct-17 Release date: 02-May-18

Protein chains

P22262  (PRFA_LISMO) -  Listeriolysin regulatory protein from Listeria monocytogenes serovar 1/2a (strain ATCC BAA-679 / EGD-e)

Seq: 237 a.a.

Struc: 230 a.a.

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1021/acs.jmedchem.8b00289

J Med Chem 61:4165-4175 (2018)

PubMed id: 29667825

Structure-Based Design of Inhibitors Targeting PrfA, the Master Virulence Regulator of Listeria monocytogenes.

M.Kulén, M.Lindgren, S.Hansen, A.G.Cairns, C.Grundström, A.Begum, I.van der Lingen, K.Brännström, M.Hall, U.H.Sauer, J.Johansson, A.E.Sauer-Eriksson, F.Almqvist.

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_I), 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_I selective PrfA inhibitors with potent antivirulence properties.