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Cryo-EM structure of Drg1 hexamer in helical state treated with ADP/AMPPNP/benzo-diazaborineCryo-EM structure of Drg1 hexamer in helical state treated with ADP/AMPPNP/benzo-diazaborine
Structural highlights
FunctionAFG2_YEAST ATP-dependent chaperone which uses the energy provided by ATP hydrolysis to generate mechanical force to disassemble protein complexes (PubMed:12006565, PubMed:17646390, PubMed:23185031, PubMed:24371142). Plays an essential role in the cytoplasmic maturation steps of pre-60S ribosomal particles by promoting the release of shuttling protein RLP24 from the pre-ribosomal particles (PubMed:17646390, PubMed:23185031, PubMed:24371142). This step facilitates the subsequent release of other shuttling proteins such as NOG1 and allows the transition of the pre-ribosomal particles to later maturation forms that bind REI1 (PubMed:17646390, PubMed:23185031, PubMed:24371142). Essential for viability (PubMed:24371142, PubMed:8109176).[1] [2] [3] [4] [5] Publication Abstract from PubMedThe 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. Structural dynamics of AAA + ATPase Drg1 and mechanism of benzo-diazaborine inhibition.,Ma C, Wu D, Chen Q, Gao N Nat Commun. 2022 Nov 9;13(1):6765. doi: 10.1038/s41467-022-34511-2. PMID:36351914[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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