Structural insight into the ligand-receptor interaction between glycyrrhetinic acid (GA) and the high-mobility group protein B1 (HMGB1)-DNA complex

Abstract

Structural analysis of the high-mobility group protein B1 (HMGB1)-DNA complex and a docking simulation between glycyrrhetinic acid (GA) and the HMGB1-DNA complex were performed with a software package the Molecular Operating Environment (MOE). An HMGB1-DNA (PDB code: 2GZK) was selected for the 3D structure modeling of the HMGB1-DNA complex. The Site Finder module of the MOE identified 16 possible ligand-binding sites in the modeled HMGB1-DNA complex. The docking simulation revealed that GA possibly inhibits functions of HMGB1 interfering with Lys(90), Arg(91), Ser(101), Tyr(149), C(230) and C(231) in the HMGB1-DNA complex. To the best of our knowledge, this is the first report of an HMGB1-DNA complex with GA, and our data verify that the GA-HMGB1-DNA model can be utilized for application to target HMGB1 for the development of antitumor drugs.

Abbreviations: ASE-Dock - alpha sphere and excluded volume-based ligand-protein docking, CNS - central nervous system, GA - glycyrrhetinic acid, GL - glycyrrhizin, HMGB1 - high-mobility group protein B1, LBS - ligand-biding site, MOE - Molecular Operating Environment, SRY - sex-determining region on the Y chromosome.

Keywords: Antitumor drug; GA; HMGB1; MOE.

Figure 1

(A) The sequence alignment of HMGB1 (PDB code: 2GZK) and the duplex containing the consensus sequence of SRY; (B) The 2D structure of the HMGB1-DNA complex. For HMGB1; Red: α-helix. Blue: turn. For DNA; Green: carbon for G²⁰¹ – C²¹⁶. Orange: carbon for G²¹⁷ – C²³². Blue: nitrogen. Purple: phosphorus. Red: oxygen.

Figure 2

(A) The 16 possible LBSs identified by the Site Finder module of the MOE; (B) The identified possible LBSs depicted with the hydrophobic (white) or hydrophilic (red) alpha spheres, which serves as probes denoting zones of tight atom packing. For HMGB1; Red: α-helix. Blue: turn. For DNA; Green: carbon for G²⁰¹ – C²¹⁶. Orange: carbon for G²¹⁷ – C²³². Blue: nitrogen. Purple: phosphorus. Red: oxygen.

Figure 3

Docking simulation of GA to the HMGB1-DNA complex. (A) ASE-Dock showing that GA binds at the No. 9 site (Figure 2A) in the HMGB1-DNA complex; (B) The enlarged figure of the LBS in the GA-HMGB1-DNA complex. For GA; Gray: carbon. For HMGB1; Red: α-helix. Blue: turn. For DNA; Green: carbon for G²⁰¹ – C²¹⁶. Orange: carbon for G²¹⁷ – C²³². Blue: nitrogen. Purple: phosphorus. Red: oxygen.

Figure 4

The ligand-receptor interaction plots for the GA-HMGB1-DNA complex created by the Ligand Interactions module of the MOE.