6O9Y

Structure of human PARG complexed with JA2-8

6O9Y の概要

• エントリーDOI: 10.2210/pdb6o9y/pdb
• 関連するPDBエントリー: 6O9X
• 分子名称: Poly(ADP-ribose) glycohydrolase, 7-[(2S)-2-hydroxy-3-(morpholin-4-yl)propyl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (3 entities in total)
• 機能のキーワード: hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 61546.98

構造登録者

Stegeman, R.A.,Jones, D.E.,Ellenberger, T.,Kim, I.K.,Tainer, J.A. (登録日: 2019-03-15, 公開日: 2019-12-25, 最終更新日: 2024-03-13)

主引用文献

Houl, J.H.,Ye, Z.,Brosey, C.A.,Balapiti-Modarage, L.P.F.,Namjoshi, S.,Bacolla, A.,Laverty, D.,Walker, B.L.,Pourfarjam, Y.,Warden, L.S.,Babu Chinnam, N.,Moiani, D.,Stegeman, R.A.,Chen, M.K.,Hung, M.C.,Nagel, Z.D.,Ellenberger, T.,Kim, I.K.,Jones, D.E.,Ahmed, Z.,Tainer, J.A.
Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death.
Nat Commun, 10:5654-5654, 2019

PubMed Abstract: Poly(ADP-ribose)ylation (PARylation) by PAR polymerase 1 (PARP1) and PARylation removal by poly(ADP-ribose) glycohydrolase (PARG) critically regulate DNA damage responses; yet, conflicting reports obscure PARG biology and its impact on cancer cell resistance to PARP1 inhibitors. Here, we found that PARG expression is upregulated in many cancers. We employed chemical library screening to identify and optimize methylxanthine derivatives as selective bioavailable PARG inhibitors. Multiple crystal structures reveal how substituent positions on the methylxanthine core dictate binding modes and inducible-complementarity with a PARG-specific tyrosine clasp and arginine switch, supporting inhibitor specificity and a competitive inhibition mechanism. Cell-based assays show selective PARG inhibition and PARP1 hyperPARylation. Moreover, our PARG inhibitor sensitizes cells to radiation-induced DNA damage, suppresses replication fork progression and impedes cancer cell survival. In PARP inhibitor-resistant A172 glioblastoma cells, our PARG inhibitor shows comparable killing to Nedaplatin, providing further proof-of-concept that selectively inhibiting PARG can impair cancer cell survival.

PubMed: 31827085
DOI: 10.1038/s41467-019-13508-4

実験手法

X-RAY DIFFRACTION (2 Å)