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Human DNA-dependent protein kinase activation mechanism.

<div class='caption-title'>Overview of DNA-PK from structures defined by cryo-EM.</div>
<div class='caption-title'>The structure of DNA-PK in the intermediate state defined by cryo-EM.</div>
<div class='caption-title'>The structure of DNA-PK in the active state defined by cryo-EM.</div>
Liang S, Blundell TL
OpenAccess logo Nat Struct Mol Biol (2023)
Cited: 7 times
EuropePMC logo PMID: 36604499

Abstract

DNA-dependent protein kinase (DNA-PK), a multicomponent complex including the DNA-PK catalytic subunit and Ku70/80 heterodimer together with DNA, is central to human DNA damage response and repair. Using a DNA-PK-selective inhibitor (M3814), we identified from one dataset two cryo-EM structures of the human DNA-PK complex in different states, the intermediate state and the active state. Here we show that activation of the kinase is regulated through conformational changes caused by the binding ligand and the string region (residues 802-846) of the DNA-PK catalytic subunit, particularly the helix-hairpin-helix motif (residues 816-836) that interacts with DNA. These observations demonstrate the regulatory role of the ligand and explain why DNA-PK is DNA dependent. Cooperation and coordination among binding partners, disordered flexible regions and mechanically flexible HEAT repeats modulate the activation of the kinase. Together with previous findings, these results provide a better molecular understanding of DNA-PK catalysis.

Articles - 7z87 mentioned but not cited (3)

  1. Human DNA-dependent protein kinase activation mechanism. Liang S, Blundell TL. Nat Struct Mol Biol 30 140-147 (2023)
  2. Synthesis, X-ray Crystal Structure, Anticancer, Hirshfeld Surface Analysis, DFT, TD-DFT, ADMET, and Molecular Docking of 3-Phenyl-1,2,4-triazolo[3,4-h]-13,4-thiaza-11-crown-4. Lazrak F, Lahmidi S, Anouar EH, Alanazi MM, Alanazi AS, Essassi EM, Mague JT. Molecules 28 3166 (2023)
  3. research-article Unravelling the complexities of DNA-PK activation by structure-based mutagenesis. Buehl CJ, Goff NJ, Mikhova M, Hardwick SW, Blundell TL, Modesti M, Schmidt JC, Chaplin A, Meek K. Res Sq rs.3.rs-3627471 (2023)


Reviews citing this publication (2)

  1. Structure and function of the apical PIKKs in double-strand break repair. Xu J, Bradley N, He Y. Curr Opin Struct Biol 82 102651 (2023)
  2. Strategies for Conditional Regulation of Proteins. Nadendla K, Simpson GG, Becher J, Journeaux T, Cabeza-Cabrerizo M, Bernardes GJL. JACS Au 3 344-357 (2023)

Articles citing this publication (2)

  1. Structural insights into the activation of ataxia-telangiectasia mutated by oxidative stress. Howes AC, Perisic O, Williams RL. Sci Adv 9 eadi8291 (2023)
  2. Structure and mechanism in non-homologous end joining. Vogt A, He Y. DNA Repair (Amst) 130 103547 (2023)


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