8EZA

NHEJ Long-range complex with PAXX

Summary for 8EZA

• Entry DOI: 10.2210/pdb8eza/pdb
• EMDB information: 28732 28735 28736
• Descriptor: Protein PAXX, DNA ligase 4, ADENOSINE-5'-TRIPHOSPHATE, ... (11 entities in total)
• Functional Keywords: complex, kinase, nhej, dna binding protein, dna binding protein-dna complex, dna binding protein/dna
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 22
• Total formula weight: 1758482.43

Authors

Chen, S.,He, Y. (deposition date: 2022-10-31, release date: 2023-06-14, Last modification date: 2024-06-19)

Primary citation

Chen, S.,Vogt, A.,Lee, L.,Naila, T.,McKeown, R.,Tomkinson, A.E.,Lees-Miller, S.P.,He, Y.
Cryo-EM visualization of DNA-PKcs structural intermediates in NHEJ.
Sci Adv, 9:eadg2838-eadg2838, 2023

PubMed Abstract: DNA double-strand breaks (DSBs), one of the most cytotoxic forms of DNA damage, can be repaired by the tightly regulated nonhomologous end joining (NHEJ) machinery (Stinson and Loparo and Zhao ). Core NHEJ factors form an initial long-range (LR) synaptic complex that transitions into a DNA-PKcs (DNA-dependent protein kinase, catalytic subunit)-free, short-range state to align the DSB ends (Chen ). Using single-particle cryo-electron microscopy, we have visualized three additional key NHEJ complexes representing different transition states, with DNA-PKcs adopting distinct dimeric conformations within each of them. Upon DNA-PKcs autophosphorylation, the LR complex undergoes a substantial conformational change, with both Ku and DNA-PKcs rotating outward to promote DNA break exposure and DNA-PKcs dissociation. We also captured a dimeric state of catalytically inactive DNA-PKcs, which resembles structures of other PIKK (Phosphatidylinositol 3-kinase-related kinase) family kinases, revealing a model of the full regulatory cycle of DNA-PKcs during NHEJ.

PubMed: 37256947
DOI: 10.1126/sciadv.adg2838

Experimental method

ELECTRON MICROSCOPY (4.39 Å)