Allosteric inhibition site of transglutaminase 2 is unveiled in the N terminus

Nayeon Kim, Joon Hee Kang, Won Kyu Lee, Seul Gi Kim, Jae Seon Lee, Seon Hyeong Lee, Jong Bae Park, Kyung Hee Kim, Young Dae Gong, Kwang Yeon Hwang, Soo Youl Kim

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


Previously we have demonstrated transglutaminase 2 (TGase 2) inhibition abrogated renal cell carcinoma (RCC) using GK921 (3-(phenylethynyl)-2-(2-(pyridin-2-yl)ethoxy)pyrido[3,2-b]pyrazine), although the mechanism of TGase 2 inhibition remains unsolved. Recently, we found that the increase of TGase 2 expression is required for p53 depletion in RCC by transporting the TGase 2 (1–139 a.a)–p53 complex to the autophagosome, through TGase 2 (472–687 a.a) binding p62. In this study, mass analysis revealed that GK921 bound to the N terminus of TGase 2 (81–116 a.a), which stabilized p53 by blocking TGase 2 binding. This suggests that RCC survival can be stopped by p53-induced cell death through blocking the p53–TGase 2 complex formation using GK921. Although GK921 does not bind to the active site of TGase 2, GK921 binding to the N terminus of TGase 2 also inactivated TGase 2 activity through acceleration of non-covalent self-polymerization of TGase 2 via conformational change. This suggests that TGase 2 has an allosteric binding site (81–116 a.a) which changes the conformation of TGase 2 enough to accelerate inactivation through self-polymer formation.

Original languageEnglish
Pages (from-to)1583-1594
Number of pages12
JournalAmino Acids
Issue number11
Publication statusPublished - 2018 Nov 1


  • Allosteric binding site
  • GK921
  • Transglutaminase 2
  • p53

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Organic Chemistry


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