Direct inhibition of the first PDZ domain of ZO-1 by glycyrrhizin is a possible mechanism of tight junction opening of Caco-2 cells

• DOI: 10.1039/d1fo03062k
• Publication Date: 2022-01-04T08:01:44Z
• Authors: Emi Hibino; Natsuko Goda; Misaki Hisada; Takeshi Tenno; Hidekazu Hiroaki
• Keywords: Glycyrrhizin; Claudin; PDZ domain

Glycyrrhizin (GL) is known to exhibit a variety of useful pharmacological activities, including anti-inflammation, anti-hepatotoxicity, and enhancement intestinal drug absorption. GL has been reported modify the assembly actin filaments, thereby modulating tight junction (TJ) integrity, but detailed molecular mechanisms this remain unclear. In study, we first found that binds PDZ domain zonula occludens-1 (ZO-1(PDZ1)) through NMR experiments. The structure GL-ZO-1(PDZ1) complex was then constructed using HADDOCK with transferred nuclear Overhauser effect-based inter-hydrogen distance constraints as well restrictions on interfacial residues identified from 1H-15N HSQC spectral changes. We relevant interactions between glucuronate-2 moiety carboxylate binding loop ligand site ZO-1(PDZ1). further examined interaction ZO-1(PDZ1) glycyrrhetinic acid GA-3-monoglucuronide observed much lower affinity for each than GL, good agreement model. other contacts in model were by an amino substitution mutant Finally, reproduced experiments Sakai et al. which high-dose prolonged TJ-opening mediated sodium deoxycholate indicated reduced transepithelial electrical resistance.