Glycyrrhizin binds to high-mobility group box 1 protein and inhibits its cytokine activities

Chem Biol. 2007 Apr;14(4):431-41. doi: 10.1016/j.chembiol.2007.03.007.

Abstract

High-mobility group box 1 protein (HMGB1) is a nuclear component, but extracellularly it serves as a signaling molecule involved in acute and chronic inflammation, for example in sepsis and arthritis. The identification of HMGB1 inhibitors is therefore of significant experimental and clinical interest. We show that glycyrrhizin, a natural anti-inflammatory and antiviral triterpene in clinical use, inhibits HMGB1 chemoattractant and mitogenic activities, and has a weak inhibitory effect on its intranuclear DNA-binding function. NMR and fluorescence studies indicate that glycyrrhizin binds directly to HMGB1 (K(d) approximately 150 microM), interacting with two shallow concave surfaces formed by the two arms of both HMG boxes. Our results explain in part the anti-inflammatory properties of glycyrrhizin, and might direct the design of new derivatives with improved HMGB1-binding properties.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / metabolism*
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Binding Sites
  • Cytokines / antagonists & inhibitors*
  • Cytokines / metabolism
  • DNA / metabolism
  • Fluorescence
  • Glycyrrhizic Acid / chemistry
  • Glycyrrhizic Acid / metabolism*
  • Glycyrrhizic Acid / pharmacology
  • HMGB1 Protein / antagonists & inhibitors*
  • HMGB1 Protein / chemistry
  • HMGB1 Protein / metabolism*
  • Humans
  • Magnetic Resonance Spectroscopy
  • Mice
  • Mitogens / antagonists & inhibitors
  • Mitogens / pharmacology
  • Models, Molecular
  • Protein Binding

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Cytokines
  • HMGB1 Protein
  • Mitogens
  • Glycyrrhizic Acid
  • DNA