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. 2022 Jun 29;607(7918):393–398. doi: 10.1038/s41586-022-04790-2

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© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Extended Data Fig. 9 — (a) Structure of the human Dicer–TRBP heterodimer bound to a pre-miRNA (pre-let-7) (PDB: 5ZAL). TRBP is shown as a surface model. RBD1 and RBD2 of TRBP are disordered in the structure and indicated by dashed circles. The human Dicer–TRBP–pre-let-7 structure represents the pre-miRNA substrate recognition state, in which the 2-nt 3′-overhanging end and the terminal loop of pre-let-7 are anchored by the Platform-PAZ domain and the interface between human Dicer Hel2i and TRBP CTD, respectively. (b) Structure of the Dicer-2–R2D2 heterodimer. R2D2 is shown as a surface model. RBD1 of R2D2 is disordered in the structure and indicated by a dashed circle. (c) Possible steric clash between R2D2 and a pre-miRNA. Dicer-2 initially recognizes a long dsRNA substrate using only the helicase domain, whereas human Dicer recognizes a pre-miRNA substrate using both the PAZ and helicase domains. Based on the hypothesis that, like human Dicer, Dicer-2 recognizes a pre-miRNA using both the PAZ and helicase domains, we modeled a pre-miRNA onto the Dicer-2–R2D2 structure, as follows. The human Dicer–TRBP–pre-miRNA (pre-let-7) structure was superimposed onto the Dicer-2–R2D2 structure based on their PAZ domains, and human Dicer and TRBP were then omitted. While Dicer-2 and human Dicer commonly associate with their partner proteins via their Hel2i–CTD interfaces, conformational differences are present in RBD1 and RBD2 of the partner proteins. RBD2 of R2D2 is ordered and interacts with the central linker and CRBD in the Dicer-2–R2D2 structure (RBD1 is disordered). In contrast, RBD1 and RBD2 of TRBP are disordered and may loosely interact with the pre-miRNA in the human Dicer–TRBP–pre-miRNA structure. A structural comparison of Dicer-2–R2D2 with human Dicer–TRBP–pre-miRNA suggested that R2D2 could sterically clash with a modeled pre-miRNA, explaining why R2D2 inhibits promiscuous pre-miRNA processing by Dicer-2.