6K95

Crystal structural of human glutathione-specific gamma-glutamylcyclotransferase 2 (ChaC2)

6K95 の概要

• エントリーDOI: 10.2210/pdb6k95/pdb
• 分子名称: Glutathione-specific gamma-glutamylcyclotransferase 2 (2 entities in total)
• 機能のキーワード: gamma-glutamylcyclotransferase, chac2, gsh degradation, swapped-domain dimer, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 62392.59

構造登録者

Nguyen, T.K.Y.,Han, B.W. (登録日: 2019-06-14, 公開日: 2020-04-22, 最終更新日: 2024-03-27)

主引用文献

Nguyen, Y.T.K.,Park, J.S.,Jang, J.Y.,Kim, K.R.,Vo, T.T.L.,Kim, K.W.,Han, B.W.
Structural and Functional Analyses of Human ChaC2 in Glutathione Metabolism.
Biomolecules, 10:-, 2019

PubMed Abstract: Glutathione (GSH) degradation plays an essential role in GSH homeostasis, which regulates cell survival, especially in cancer cells. Among human GSH degradation enzymes, the ChaC2 enzyme acts on GSH to form 5-l-oxoproline and Cys-Gly specifically in the cytosol. Here, we report the crystal structures of ChaC2 in two different conformations and compare the structural features with other known γ-glutamylcyclotransferase enzymes. The unique flexible loop of ChaC2 seems to function as a gate to achieve specificity for GSH binding and regulate the constant GSH degradation rate. Structural and biochemical analyses of ChaC2 revealed that Glu74 and Glu83 play crucial roles in directing the conformation of the enzyme and in modulating the enzyme activity. Based on a docking study of GSH to ChaC2 and binding assays, we propose a substrate-binding mode and catalytic mechanism. We also found that overexpression of ChaC2, but not mutants that inhibit activity of ChaC2, significantly promoted breast cancer cell proliferation, suggesting that the GSH degradation by ChaC2 affects the growth of breast cancer cells. Our structural and functional analyses of ChaC2 will contribute to the development of inhibitors for the ChaC family, which could effectively regulate the progression of GSH degradation-related cancers.

PubMed: 31878259
DOI: 10.3390/biom10010031

実験手法

X-RAY DIFFRACTION (2.29 Å)