9L4C

ATR Spiral -ATRIP bound with RP-3500

Summary for 9L4C

• Entry DOI: 10.2210/pdb9l4c/pdb
• EMDB information: 62809
• Descriptor: Serine/threonine-protein kinase ATR, ATR-interacting protein, ZINC ION (3 entities in total)
• Functional Keywords: atr spiral atrip rp-3500, cell cycle
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 775525.71

Authors

Wang, G. (deposition date: 2024-12-20, release date: 2025-05-21, Last modification date: 2025-07-09)

Primary citation

Wang, G.,Wang, P.,Zheng, Z.,Zhang, Q.,Xu, C.,Xu, X.,Jian, L.,Zhao, Z.,Cai, G.,Wang, X.
Molecular architecture and inhibition mechanism of human ATR-ATRIP.
Sci Bull (Beijing), 70:2137-2146, 2025

PubMed Abstract: The ataxia telangiectasia-mutated and Rad3-related (ATR) kinase is a master regulator of DNA damage response and replication stress in humans. Targeting ATR is the focus of oncology drug pipelines with a number of potent, selective ATR inhibitors currently in clinical development. Here, we determined the cryo-EM structures of the human ATR-ATRIP complex in the presence of VE-822 and RP-3500, two ATR inhibitors currently in Phase II clinical trials, achieving an overall resolution of approximately 3 Å. These structures yield a near-complete atomic model of the ATR-ATRIP complex, revealing subunit stoichiometry, intramolecular and intermolecular interactions, and critical regulatory sites including an insertion in the PIKK regulatory domain (PRD). Structural comparison provides insights into the modes of action and selectivity of ATR inhibitors. The divergent binding modes near the solvent side and in the rear pocket area of VE-822 and RP-3500, particularly their disparate binding orientations, lead to varying conformational changes in the active site. Surprisingly, one ATR-ATRIP complex binds four VE-822 molecules, with two in the ATR active site and two at the ATR-ATR dimer interface. The binding and selectivity of RP-3500 depend on two bound water molecules, which may be further enhanced by the substitution of these bound waters. Our study provides a structural framework for understanding ATR regulation and holds promise for assisting future efforts in rational drug design targeting ATR.

PubMed: 40379520
DOI: 10.1016/j.scib.2025.05.009

Experimental method

ELECTRON MICROSCOPY (4.06 Å)