Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Molecular architecture and inhibition mechanism of human ATR-ATRIP.
Journal, issue, pages	Sci Bull (Beijing), Vol. 70, Issue 13, Page 2137-2146, Year 2025
Publish date	Jul 15, 2025
Authors	Guangxian Wang / Po Wang / Zexuan Zheng / Qingjun Zhang / Chenchen Xu / Xinyi Xu / Lingfei Jian / Zhanpeng Zhao / Gang Cai / Xuejuan Wang /
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 ...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.
External links	Sci Bull (Beijing) / PubMed:40379520
Methods	EM (single particle)
Resolution	2.87 - 6.29 Å
Structure data	62801 9l40 EMDB-62801, PDB-9l40: kinase of ATR bound VE-822 state Method: EM (single particle) / Resolution: 2.87 Å 62804 9l43 EMDB-62804, PDB-9l43: ATR Spiral -ATRIP bound with VE-822 Method: EM (single particle) / Resolution: 3.83 Å 62806 9l45 EMDB-62806, PDB-9l45: ATR-ATRIP bound with VE-822 Method: EM (single particle) / Resolution: 3.95 Å 62807 9l46 EMDB-62807, PDB-9l46: ATR-ATRIP-bound with AMP-PNP Method: EM (single particle) / Resolution: 6.29 Å 62808 9l4b EMDB-62808, PDB-9l4b: Kinase domain of ATR bound with RP-3500 Method: EM (single particle) / Resolution: 3.2 Å 62809 9l4c EMDB-62809, PDB-9l4c: ATR Spiral -ATRIP bound with RP-3500 Method: EM (single particle) / Resolution: 4.06 Å 62811 9l4d EMDB-62811, PDB-9l4d: ATR-ATRIP bound with RP-3500 Method: EM (single particle) / Resolution: 3.79 Å 62812 9l4f EMDB-62812, PDB-9l4f: ATR-ATRIP bound with ATPgammaS Method: EM (single particle) / Resolution: 6.22 Å
Chemicals	PDB-1eie: CRYSTAL STRUCTURE OF F120W MUTANT OF BOVINE PANCREATIC RIBONUCLEASE A ChemComp-ZN: Unknown entry ChemComp-AGS: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-gamma-S, energy-carrying molecule analogueYM PDB-1eik: Solution Structure of RNA Polymerase Subunit RPB5 from Methanobacterium Thermoautotrophicum ChemComp-HOH*: WATER
Source	homo sapiens (human)
Keywords	CELL CYCLE / inhibitor / ATR / kinase / ATR spiral / ATRIP / ATR-ATRIP inhibitor / ATR inhibitor / ATR spiral ATRIP RP-3500 / ATR-ATRIP ATPgammaS