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Title | Structural dynamics of AAA + ATPase Drg1 and mechanism of benzo-diazaborine inhibition. |
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Journal, issue, pages | Nat Commun, Vol. 13, Issue 1, Page 6765, Year 2022 |
Publish date | Nov 9, 2022 |
Authors | Chengying Ma / Damu Wu / Qian Chen / Ning Gao / |
PubMed 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 ...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. |
External links | Nat Commun / PubMed:36351914 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.6 - 5.9 Å |
Structure data | EMDB-32396, PDB-7wbb: EMDB-32397: The Cryo-EM structure of Drg1 hexamer treated with ADP EMDB-32399: The Cryo-EM structure of Drg1 hexamer treated with AMPPNP EMDB-32400: The Cryo-EM structure of Drg1 hexamer in helical state treated with ADP/AMPPNP/benzo-diazaborine EMDB-32402: The Cryo-EM structure of Drg1 hexamer in planar state treated with ADP/AMPPNP/benzo-diazaborine EMDB-32403: Cryo-EM structure of Drg1 hexamer treated with ATP/benzo-diazaborine |
Chemicals | ChemComp-ATP: ChemComp-NDT: ChemComp-ADP: |
Source |
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Keywords | ATP-binding protein / cryo-EM structure of Drg1 / RIBOSOME / Drg1 / RIBOSOMAL PROTEIN / Involved in maturation of pre-60S ribosomal particles |