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Crystal structure of inhibitor of κB kinase β

Author

Listed:
  • Guozhou Xu

    (Weill Cornell Medical College)

  • Yu-Chih Lo

    (Weill Cornell Medical College)

  • Qiubai Li

    (Weill Cornell Medical College)

  • Gennaro Napolitano

    (University of California at San Diego)

  • Xuefeng Wu

    (University of California at San Diego)

  • Xuliang Jiang

    (EMD Serono Research Institute)

  • Michel Dreano

    (Merck Serono, Geneva 1211, Switzerland)

  • Michael Karin

    (University of California at San Diego)

  • Hao Wu

    (Weill Cornell Medical College)

Abstract

Inhibitor of κB (IκB) kinase (IKK) phosphorylates IκB proteins, leading to their degradation and the liberation of nuclear factor κB for gene transcription. Here we report the crystal structure of IKKβ in complex with an inhibitor, at a resolution of 3.6 Å. The structure reveals a trimodular architecture comprising the kinase domain, a ubiquitin-like domain (ULD) and an elongated, α-helical scaffold/dimerization domain (SDD). Unexpectedly, the predicted leucine zipper and helix–loop–helix motifs do not form these structures but are part of the SDD. The ULD and SDD mediate a critical interaction with IκBα that restricts substrate specificity, and the ULD is also required for catalytic activity. The SDD mediates IKKβ dimerization, but dimerization per se is not important for maintaining IKKβ activity and instead is required for IKKβ activation. Other IKK family members, IKKα, TBK1 and IKK-i, may have a similar trimodular architecture and function.

Suggested Citation

  • Guozhou Xu & Yu-Chih Lo & Qiubai Li & Gennaro Napolitano & Xuefeng Wu & Xuliang Jiang & Michel Dreano & Michael Karin & Hao Wu, 2011. "Crystal structure of inhibitor of κB kinase β," Nature, Nature, vol. 472(7343), pages 325-330, April.
  • Handle: RePEc:nat:nature:v:472:y:2011:i:7343:d:10.1038_nature09853
    DOI: 10.1038/nature09853
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    Cited by:

    1. Changqing Li & Stefano Moro & Kateryna Shostak & Francis J. O’Reilly & Mariel Donzeau & Andrea Graziadei & Alastair G. McEwen & Dominique Desplancq & Pierre Poussin-Courmontagne & Thomas Bachelart & M, 2024. "Molecular mechanism of IKK catalytic dimer docking to NF-κB substrates," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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