21CB

Cryo-EM structure of DICER with pre-mir-517a-GU in pre-dicing state

Summary for 21CB

• Entry DOI: 10.2210/pdb21cb/pdb
• Related: 9V42 9V43
• EMDB information: 67570
• Descriptor: Endoribonuclease Dicer, RNA (58-MER) (2 entities in total)
• Functional Keywords: endoribonuclease dicer, rna, mirna, precursor mirna, hydrolase, hydrolase-rna complex, hydrolase/rna
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 237610.64

Authors

Ngo, M.K. (deposition date: 2025-12-07, release date: 2026-03-11, Last modification date: 2026-03-18)

Primary citation

Ngo, M.K.,Le, C.T.,Nguyen, T.A.
DICER cleavage fidelity is governed by 5'-end binding pockets.
Nature, 2026

PubMed Abstract: RNA interference (RNAi) depends on DICER, an essential enzyme that processes RNA precursors into small regulatory RNAs. DICER cleaves RNA precursors according to the 5'-end counting rule, in which RNA length is measured from the 5'-end. Previous work proposed a single 5'-end binding pocket that disfavours guanosine (5'-G), leading to cleavage inaccuracies. Here we show that 5'-G promotes precise cleavage for many substrates. Using massively parallel dicing assays and cryo-electron microscopy, we identify a conserved guanosine-favoured (G-favoured) binding pocket in DICER, distinct from the previously described uridine-favoured (U-favoured) pocket. Together, these pockets influence the alignment between 21-nucleotide and 22-nucleotide cleavage registers, expanding the mechanism of small-RNA biogenesis in metazoan DICERs. We also find that conflicts between 5'-end binding and RNA-motif recognition can trigger RNA conformational adjustments that preserve accurate cleavage-site selection. In addition, conformational adjustments of the double-stranded RNA-binding domain (dsRBD) and PAZ domain help to align substrates with the catalytic centres for precise double-strand cleavage. These results show that the DICER cleavage mechanism integrates dual 5'-end binding pockets, RNA-motif influence and domain motions, advancing our understanding of microRNA biogenesis.

PubMed: 41781616
DOI: 10.1038/s41586-026-10211-5

Experimental method

ELECTRON MICROSCOPY (3 Å)