Structural Basis for the Inhibition of the Autophosphorylation Activity of HK853 by Luteolin

Molecules. 2019 Mar 7;24(5):933. doi: 10.3390/molecules24050933.


The two-component system (TCS) is a significant signal transduction system for bacteria to adapt to complicated and variable environments, and thus has recently been regarded as a novel target for developing antibacterial agents. The natural product luteolin (Lut) can inhibit the autophosphorylation activity of the typical histidine kinase (HK) HK853 from Thermotoga maritime, but the inhibition mechanism is not known. Herein, we report on the binding mechanism of a typical flavone with HK853 by using solution NMR spectroscopy, isothermal titration calorimetry (ITC), and molecular docking. We show that luteolin inhibits the activity of HK853 by occupying the binding pocket of adenosine diphosphate (ADP) through hydrogen bonds and π-π stacking interaction structurally. Our results reveal a detailed mechanism for the inhibition of flavones and observe the conformational and dynamics changes of HK. These results should provide a feasible approach for antibacterial agent design from the view of the histidine kinases.

Keywords: ATP; NMR; histidine kinase; inhibition; luteolin; molecular docking; two-component system.

MeSH terms

  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / chemistry
  • Calorimetry
  • Histidine Kinase / antagonists & inhibitors*
  • Histidine Kinase / chemistry*
  • Hydrogen Bonding
  • Luteolin / pharmacology*
  • Models, Molecular
  • Molecular Docking Simulation
  • Nuclear Magnetic Resonance, Biomolecular
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Protein Conformation
  • Thermotoga maritima / chemistry
  • Thermotoga maritima / enzymology*


  • Bacterial Proteins
  • Histidine Kinase
  • Luteolin