EMD-11215
Cryo-EM structure of DNA-PKcs:Ku80ct194
EMD-11215
Single-particle3.93 Å
Deposition: 21/06/2020Map released: 21/10/2020
Last modified: 01/05/2024
Sample Organism:
Homo sapiens
Sample: DNA-PKcs in complex with Ku80 C-terminal domain
Fitted models: 6zh6 (Avg. Q-score: 0.335)
Deposition Authors: Chaplin AK, Hardwick SW
Sample: DNA-PKcs in complex with Ku80 C-terminal domain
Fitted models: 6zh6 (Avg. Q-score: 0.335)
Deposition Authors: Chaplin AK, Hardwick SW
Dimers of DNA-PK create a stage for DNA double-strand break repair.
Chaplin AK,
Hardwick SW ,
Liang S ,
Kefala Stavridi A,
Hnizda A ,
Cooper LR,
De Oliveira TM,
Chirgadze DY ,
Blundell TL
(2021) Nat Struct Mol Biol , 28 , 13 - 19
,
Liang S ,
Kefala Stavridi A,
Hnizda A ,
Cooper LR,
De Oliveira TM,
Chirgadze DY ,
Blundell TL
(2021) Nat Struct Mol Biol , 28 , 13 - 19
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.
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.