7SID

Human ATM Dimer Bound to Nbs1

7SID の概要

• エントリーDOI: 10.2210/pdb7sid/pdb
• EMDBエントリー: 25141
• 分子名称: Serine-protein kinase ATM, Nibrin, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (4 entities in total)
• 機能のキーワード: kinase, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 710346.27

構造登録者

Warren, C.,Pavletich, N.P. (登録日: 2021-10-13, 公開日: 2022-02-02, 最終更新日: 2024-06-05)

主引用文献

Warren, C.,Pavletich, N.P.
Structure of the human ATM kinase and mechanism of Nbs1 binding.
Elife, 11:-, 2022

PubMed Abstract: DNA double-strand breaks (DSBs) can lead to mutations, chromosomal rearrangements, genome instability, and cancer. Central to the sensing of DSBs is the ATM (Ataxia-telangiectasia mutated) kinase, which belongs to the phosphatidylinositol 3-kinase-related protein kinase (PIKK) family. In response to DSBs, ATM is activated by the MRN (Mre11-Rad50-Nbs1) protein complex through a poorly understood process that also requires double-stranded DNA. Previous studies indicate that the FxF/Y motif of Nbs1 directly binds to ATM, and is required to retain active ATM at sites of DNA damage. Here, we report the 2.5 Å resolution cryo-EM structures of human ATM and its complex with the Nbs1 FxF/Y motif. In keeping with previous structures of ATM and its yeast homolog Tel1, the dimeric human ATM kinase adopts a symmetric, butterfly-shaped structure. The conformation of the ATM kinase domain is most similar to the inactive states of other PIKKs, suggesting that activation may involve an analogous realigning of the N and C lobes along with relieving the blockage of the substrate-binding site. We also show that the Nbs1 FxF/Y motif binds to a conserved hydrophobic cleft within the Spiral domain of ATM, suggesting an allosteric mechanism of activation. We evaluate the importance of these structural findings with mutagenesis and biochemical assays.

PubMed: 35076389
DOI: 10.7554/eLife.74218

実験手法

ELECTRON MICROSCOPY (2.53 Å)