6OA1

Structure of human PARG complexed with JA2120

Summary for 6OA1

• Entry DOI: 10.2210/pdb6oa1/pdb
• Related: 6O9X 6O9Y 6OA0
• Descriptor: Poly(ADP-ribose) glycohydrolase, 1,3-dimethyl-8-{[2-(morpholin-4-yl)ethyl]sulfanyl}-3,7-dihydro-1H-purine-2,6-dione (3 entities in total)
• Functional Keywords: hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 61549.02

Authors

Stegeman, R.A.,Jones, D.E.,Ellenberger, T.,Kim, I.K.,Tainer, J.A. (deposition date: 2019-03-15, release date: 2019-12-25, Last modification date: 2024-03-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.8 Å)