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Structure of a repair enzyme interrogating undamaged DNA elucidates recognition of damaged DNA

Author

Listed:
  • Anirban Banerjee

    (Departments of Chemistry and Chemical Biology)

  • Wei Yang

    (Departments of Chemistry and Chemical Biology)

  • Martin Karplus

    (Departments of Chemistry and Chemical Biology
    Université Louis Pasteur)

  • Gregory L. Verdine

    (Departments of Chemistry and Chemical Biology
    Harvard University)

Abstract

How DNA repair proteins distinguish between the rare sites of damage and the vast expanse of normal DNA is poorly understood. Recognizing the mutagenic lesion 8-oxoguanine (oxoG) represents an especially formidable challenge, because this oxidized nucleobase differs by only two atoms from its normal counterpart, guanine (G). Here we report the use of a covalent trapping strategy to capture a human oxoG repair protein, 8-oxoguanine DNA glycosylase I (hOGG1), in the act of interrogating normal DNA. The X-ray structure of the trapped complex features a target G nucleobase extruded from the DNA helix but denied insertion into the lesion recognition pocket of the enzyme. Free energy difference calculations show that both attractive and repulsive interactions have an important role in the preferential binding of oxoG compared with G to the active site. The structure reveals a remarkably effective gate-keeping strategy for lesion discrimination and suggests a mechanism for oxoG insertion into the hOGG1 active site.

Suggested Citation

  • Anirban Banerjee & Wei Yang & Martin Karplus & Gregory L. Verdine, 2005. "Structure of a repair enzyme interrogating undamaged DNA elucidates recognition of damaged DNA," Nature, Nature, vol. 434(7033), pages 612-618, March.
    • Handle: RePEc:nat:nature:v:434:y:2005:i:7033:d:10.1038_nature03458
    DOI: 10.1038/nature03458
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    Cited by:

    1. Tatu Pantsar & Sami Rissanen & Daniel Dauch & Tuomo Laitinen & Ilpo Vattulainen & Antti Poso, 2018. "Assessment of mutation probabilities of KRAS G12 missense mutants and their long-timescale dynamics by atomistic molecular simulations and Markov state modeling," PLOS Computational Biology, Public Library of Science, vol. 14(9), pages 1-23, September.
    2. L. Tanner & A. B. Single & R. K. V. Bhongir & M. Heusel & T. Mohanty & C. A. Q. Karlsson & L. Pan & C-M. Clausson & J. Bergwik & K. Wang & C. K. Andersson & R. M. Oommen & J. S. Erjefält & J. Malmströ, 2023. "Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis in a murine lung fibrosis model," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Mengtian Ren & Fabian Gut & Yilan Fan & Jingke Ma & Xiajing Shan & Aysenur Yikilmazsoy & Mariia Likhodeeva & Karl-Peter Hopfner & Chuanzheng Zhou, 2024. "Structural basis for human OGG1 processing 8-oxodGuo within nucleosome core particles," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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