13DE

Cryo-EM structure of ATR-ATRIP-ETAA1 AAD (S95D/S111D)

13DE の概要

• エントリーDOI: 10.2210/pdb13de/pdb
• EMDBエントリー: 76990
• 分子名称: Serine/threonine-protein kinase ATR, ATR-interacting protein, Ewing's tumor-associated antigen 1, ... (6 entities in total)
• 機能のキーワード: kinase, pi3k-related kinase, complex, activator, replication stress response, replication checkpoint, nuclear protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 832381.95

構造登録者

Li, B.,Pavletich, N.P. (登録日: 2026-04-30, 公開日: 2026-08-05)

主引用文献

Li, B.,Yaseen, A.,Pavletich, N.P.
Structural mechanism of TOPBP1 activating the ATR-ATRIP replication checkpoint kinase.
Nat.Struct.Mol.Biol., 2026

PubMed Abstract: The ATR protein kinase preserves genomic integrity during DNA replication by controlling checkpoints needed for the orderly progression of S phase and for the responses to replication stress. ATR, with its obligate partner ATRIP, is activated by the TOPBP1 and ETAA1 proteins, which control different branches of ATR signaling. TOPBP1 is essential for induction of the S phase checkpoint in response to stalled replication forks, while ETAA1 is required for timely progression to mitosis from an unperturbed S phase. TOPBP1 and ETAA1 contain ATR-activating domains (AADs) of limited homology, but how they activate ATR has not yet been fully elucidated. Here we present the 3.0-Å cryo-EM structure of the human ATR-ATRIP complex bound to the TOPBP1 AAD, showing that TOPBP1 activates ATR by inducing a global conformational change that allosterically realigns active site residues in the kinase domain ~70 Å away. We also present the 3.3-Å structure of the ATR-ATRIP-ETAA1 AAD complex, which reveals a binding mode distinct from TOPBP1. Our data suggest that the distinct binding modes of TOPBP1 and ETAA1 contribute to the different cellular contexts and outcomes of ATR-ATRIP activation.

PubMed: 42493622
DOI: 10.1038/s41594-026-01844-1

実験手法

ELECTRON MICROSCOPY (2.9 Å)