6ZH4

Cryo-EM structure of DNA-PKcs (State 3)

Summary for 6ZH4

• Entry DOI: 10.2210/pdb6zh4/pdb
• EMDB information: 11213
• Descriptor: DNA-dependent protein kinase catalytic subunit,DNA-PKcs (1 entity in total)
• Functional Keywords: kinase, dna-pkcs, nhej, dna-repair, dna-pk, dna binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 472056.28

Authors

Chaplin, A.K.,Hardwick, S.W.,Chirgadze, D.Y.,Blundell, T.L. (deposition date: 2020-06-20, release date: 2020-10-21, Last modification date: 2024-05-01)

Primary citation

Chaplin, A.K.,Hardwick, S.W.,Liang, S.,Kefala Stavridi, A.,Hnizda, A.,Cooper, L.R.,De Oliveira, T.M.,Chirgadze, D.Y.,Blundell, T.L.
Dimers of DNA-PK create a stage for DNA double-strand break repair.
Nat.Struct.Mol.Biol., 28:13-19, 2021

PubMed Abstract: DNA double-strand breaks are the most dangerous type of DNA damage and, if not repaired correctly, can lead to cancer. In humans, Ku70/80 recognizes DNA broken ends and recruits the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form DNA-dependent protein kinase holoenzyme (DNA-PK) in the process of non-homologous end joining (NHEJ). We present a 2.8-Å-resolution cryo-EM structure of DNA-PKcs, allowing precise amino acid sequence registration in regions uninterpreted in previous 4.3-Å X-ray maps. We also report a cryo-EM structure of DNA-PK at 3.5-Å resolution and reveal a dimer mediated by the Ku80 C terminus. Central to dimer formation is a domain swap of the conserved C-terminal helix of Ku80. Our results suggest a new mechanism for NHEJ utilizing a DNA-PK dimer to bring broken DNA ends together. Furthermore, drug inhibition of NHEJ in combination with chemo- and radiotherapy has proved successful, making these models central to structure-based drug targeting efforts.

PubMed: 33077952
DOI: 10.1038/s41594-020-00517-x

Experimental method

ELECTRON MICROSCOPY (3.62 Å)