4.7 Article

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

期刊

FOOD & FUNCTION
卷 13, 期 4, 页码 1953-1964

出版社

ROYAL SOC CHEMISTRY
DOI: 10.1039/d1fo03062k

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资金

  1. Japan Science and Technology Agency, the A-step Feasibility Study Program [AS262Z01275Q, AS242Z00566Q]
  2. Japan Society for the Promotion of Science KAKENHI [15H04337]
  3. AMED Translational Research Program
  4. Strategic PRomotion for practical application of INnovative medical Technology (TR-SPRINT) [20lm0203011-j0002]
  5. Grants-in-Aid for Scientific Research [15H04337] Funding Source: KAKEN

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

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