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Structural dynamics of AAA + ATPase Drg1 and mechanism of benzo-diazaborine inhibition

Author

Listed:
  • Chengying Ma

    (Peking University
    Changping Laboratory)

  • Damu Wu

    (Peking University)

  • Qian Chen

    (Peking University)

  • Ning Gao

    (Peking University
    Changping Laboratory
    Peking University)

Abstract

The type II AAA + ATPase Drg1 is a ribosome assembly factor, functioning to release Rlp24 from the pre-60S particle just exported from nucleus, and its activity in can be inhibited by a drug molecule diazaborine. However, molecular mechanisms of Drg1-mediated Rlp24 removal and diazaborine-mediated inhibition are not fully understood. Here, we report Drg1 structures in different nucleotide-binding and benzo-diazaborine treated states. Drg1 hexamers transits between two extreme conformations (planar or helical arrangement of protomers). By forming covalent adducts with ATP molecules in both ATPase domain, benzo-diazaborine locks Drg1 hexamers in a symmetric and non-productive conformation to inhibits both inter-protomer and inter-ring communication of Drg1 hexamers. We also obtained a substrate-engaged mutant Drg1 structure, in which conserved pore-loops form a spiral staircase to interact with the polypeptide through a sequence-independent manner. Structure-based mutagenesis data highlight the functional importance of the pore-loop, the D1-D2 linker and the inter-subunit signaling motif of Drg1, which share similar regulatory mechanisms with p97. Our results suggest that Drg1 may function as an unfoldase that threads a substrate protein within the pre-60S particle.

Suggested Citation

  • Chengying Ma & Damu Wu & Qian Chen & Ning Gao, 2022. "Structural dynamics of AAA + ATPase Drg1 and mechanism of benzo-diazaborine inhibition," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34511-2
    DOI: 10.1038/s41467-022-34511-2
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    References listed on IDEAS

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    1. Shan Wu & Beril Tutuncuoglu & Kaige Yan & Hailey Brown & Yixiao Zhang & Dan Tan & Michael Gamalinda & Yi Yuan & Zhifei Li & Jelena Jakovljevic & Chengying Ma & Jianlin Lei & Meng-Qiu Dong & John L. Wo, 2016. "Diverse roles of assembly factors revealed by structures of late nuclear pre-60S ribosomes," Nature, Nature, vol. 534(7605), pages 133-137, June.
    2. Minglei Zhao & Shenping Wu & Qiangjun Zhou & Sandro Vivona & Daniel J. Cipriano & Yifan Cheng & Axel T. Brunger, 2015. "Mechanistic insights into the recycling machine of the SNARE complex," Nature, Nature, vol. 518(7537), pages 61-67, February.
    3. Alexandrea N. Rizo & JiaBei Lin & Stephanie N. Gates & Eric Tse & Stephen M. Bart & Laura M. Castellano & Frank DiMaio & James Shorter & Daniel R. Southworth, 2019. "Structural basis for substrate gripping and translocation by the ClpB AAA+ disaggregase," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    4. Michael Prattes & Irina Grishkovskaya & Victor-Valentin Hodirnau & Ingrid Rössler & Isabella Klein & Christina Hetzmannseder & Gertrude Zisser & Christian C. Gruber & Karl Gruber & David Haselbach & H, 2021. "Structural basis for inhibition of the AAA-ATPase Drg1 by diazaborine," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    5. Yang Xu & Han Han & Ian Cooney & Yuxuan Guo & Noah G. Moran & Nathan R. Zuniga & John C. Price & Christopher P. Hill & Peter S. Shen, 2022. "Active conformation of the p97-p47 unfoldase complex," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
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