Iwasaki, S. et al. Hsc70/Hsp90 chaperone machinery mediates ATP-dependent RISC loading of small RNA duplexes. Mol. Cell 39, 292–299 (2010).

Article 
CAS 
PubMed 

Google Scholar
 

Miyoshi, T., Takeuchi, A., Siomi, H. & Siomi, M. C. A direct role for Hsp90 in pre-RISC formation in Drosophila. Nat. Struct. Mol. Biol. 17, 1024–1026 (2010).

Article 
CAS 
PubMed 

Google Scholar
 

Iki, T. et al. In vitro assembly of plant RNA-induced silencing complexes facilitated by molecular chaperone HSP90. Mol. Cell 39, 282–291 (2010).

Article 
CAS 
PubMed 

Google Scholar
 

Kim, H., Lee, Y.-Y. & Kim, V. N. The biogenesis and regulation of animal microRNAs. Nat. Rev. Mol. Cell Biol. 26, 276–296 (2025).

Article 
CAS 
PubMed 

Google Scholar
 

Matranga, C., Tomari, Y., Shin, C., Bartel, D. P. & Zamore, P. D. Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes. Cell 123, 607–620 (2005).

Article 
ADS 
CAS 
PubMed 

Google Scholar
 

Schirle, N. T. & MacRae, I. J. The crystal structure of human Argonaute2. Science 336, 1037–1040 (2012).

Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Elkayam, E. et al. The structure of human argonaute-2 in complex with miR-20a. Cell 150, 233 (2012).

Article 
CAS 

Google Scholar
 

Song, J.-J., Smith, S. K., Hannon, G. J. & Joshua-Tor, L. Crystal structure of Argonaute and its implications for RISC slicer activity. Science 305, 1434–1437 (2004).

Article 
ADS 
CAS 
PubMed 

Google Scholar
 

Iwakawa, H.-O. & Tomari, Y. Life of RISC: formation, action, and degradation of RNA-induced silencing complex. Mol. Cell 82, 30–43 (2022).

Article 
CAS 
PubMed 

Google Scholar
 

Kirschke, E., Goswami, D., Southworth, D., Griffin, P. R. & Agard, D. A. Glucocorticoid receptor function regulated by coordinated action of the Hsp90 and Hsp70 chaperone cycles. Cell 157, 1685–1697 (2014).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Wang, R. Y.-R. et al. Structure of Hsp90-Hsp70-Hop-GR reveals the Hsp90 client-loading mechanism. Nature 601, 460–464 (2022).

Article 
ADS 
CAS 
PubMed 

Google Scholar
 

Noddings, C. M., Wang, R. Y.-R., Johnson, J. L. & Agard, D. A. Structure of Hsp90-p23-GR reveals the Hsp90 client-remodelling mechanism. Nature 601, 465–469 (2022).

Article 
ADS 
CAS 
PubMed 

Google Scholar
 

Iwasaki, S. et al. Defining fundamental steps in the assembly of the Drosophila RNAi enzyme complex. Nature 521, 533–536 (2015).

Article 
ADS 
CAS 
PubMed 

Google Scholar
 

Naruse, K., Matsuura-Suzuki, E., Watanabe, M., Iwasaki, S. & Tomari, Y. In vitro reconstitution of chaperone-mediated human RISC assembly. RNA 24, 6–11 (2018).

Article 
CAS 
PubMed 

Google Scholar
 

Tsuboyama, K., Tadakuma, H. & Tomari, Y. Conformational activation of Argonaute by distinct yet coordinated actions of the Hsp70 and Hsp90 chaperone systems. Mol. Cell 70, 722–729 (2018).

Article 
CAS 
PubMed 

Google Scholar
 

Liu, J. et al. Argonaute2 is the catalytic engine of mammalian RNAi. Science 305, 1437–1441 (2004).

Article 
ADS 
CAS 
PubMed 

Google Scholar
 

Landthaler, M. et al. Molecular characterization of human Argonaute-containing ribonucleoprotein complexes and their bound target mRNAs. RNA 14, 2580–2596 (2008).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Verba, K. A. et al. Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase. Science 352, 1542–1547 (2016).

Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Suzuki, H. I. et al. Small-RNA asymmetry is directly driven by mammalian Argonautes. Nat. Struct. Mol. Biol. 22, 512–521 (2015).

Article 
ADS 
CAS 
PubMed 

Google Scholar
 

Winter, J. & Diederichs, S. Argonaute-3 activates the let-7a passenger strand microRNA. RNA Biol. 10, 1631–1643 (2013).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Kobayashi, H., Shoji, K., Kiyokawa, K., Negishi, L. & Tomari, Y. Iruka eliminates dysfunctional Argonaute by selective ubiquitination of its empty state. Mol. Cell 73, 119–129 (2019).

Article 
CAS 
PubMed 

Google Scholar
 

Nakanishi, K., Weinberg, D. E., Bartel, D. P. & Patel, D. J. Structure of yeast Argonaute with guide RNA. Nature 486, 368–374 (2012).

Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Lee, K. et al. The structure of an Hsp90-immunophilin complex reveals cochaperone recognition of the client maturation state. Mol. Cell 81, 3496–3508 (2021).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Gruszczyk, J. et al. Cryo-EM structure of the agonist-bound Hsp90-XAP2-AHR cytosolic complex. Nat. Commun. 13, 7010 (2022).

Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

García-Alonso, S. et al. Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation. Mol. Cell 82, 3438–3452 (2022).

Article 
PubMed 

Google Scholar
 

Oberoi, J. et al. HSP90-CDC37-PP5 forms a structural platform for kinase dephosphorylation. Nat. Commun. 13, 7343 (2022).

Article 
ADS 
PubMed 
PubMed Central 

Google Scholar
 

Schirle, N. T., Sheu-Gruttadauria, J., Chandradoss, S. D., Joo, C. & MacRae, I. J. Water-mediated recognition of t1-adenosine anchors Argonaute2 to microRNA targets. eLife 4, e07646 (2015).

Article 
PubMed 
PubMed Central 

Google Scholar
 

Schirle, N. T., Sheu-Gruttadauria, J. & MacRae, I. J. Structural basis for microRNA targeting. Science 346, 608–613 (2014).

Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Mohamed, A. A., Wang, P. Y., Bartel, D. P. & Vos, S. M. The structural basis for RNA slicing by human Argonaute2. Cell Rep. 44, 115166 (2025).

Article 
CAS 
PubMed 

Google Scholar
 

Rinaldi, S., Colombo, G. & Paladino, A. Mechanistic model for the Hsp90-driven opening of human Argonaute. J. Chem. Inf. Model. 60, 1469–1480 (2020).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Abramson, J. et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3. Nature 630, 493–500 (2024).

Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Sheu-Gruttadauria, J. & MacRae, I. J. Phase transitions in the assembly and function of human miRISC. Cell 173, 946–957 (2018).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Noddings, C. M., Johnson, J. L. & Agard, D. A. Cryo-EM reveals how Hsp90 and FKBP immunophilins co-regulate the glucocorticoid receptor. Nat. Struct. Mol. Biol. 30, 1867–1877 (2023).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Jaime-Garza, M. et al. Hsp90 provides a platform for kinase dephosphorylation by PP5. Nat. Commun. 14, 2197 (2023).

Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Ali, M. M. U. et al. Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex. Nature 440, 1013–1017 (2006).

Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Taipale, M. et al. Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 150, 987–1001 (2012).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Martinez, J., Patkaniowska, A., Urlaub, H., Lührmann, R. & Tuschl, T. Single-stranded antisense siRNAs guide target RNA cleavage in RNAi. Cell 110, 563–574 (2002).

Article 
ADS 
CAS 
PubMed 

Google Scholar
 

Schirle, N. T. et al. Structural analysis of human Argonaute-2 bound to a modified siRNA guide. J. Am. Chem. Soc. 138, 8694–8697 (2016).

Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Tang, Q. & Khvorova, A. RNAi-based drug design: considerations and future directions. Nat. Rev. Drug Discov. 23, 341–364 (2024).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Foster, D. J. et al. Advanced siRNA designs further improve in vivo performance of GalNAc-siRNA conjugates. Mol. Ther. 26, 708–717 (2018).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Zheng, J. et al. Single modification at position 14 of siRNA strand abolishes its gene-silencing activity by decreasing both RISC loading and target degradation. FASEB J. 27, 4017–4026 (2013).

Article 
ADS 
CAS 
PubMed 

Google Scholar
 

Hu, B. et al. Therapeutic siRNA: state of the art. Signal Transduct. Target. Ther. 5, 101 (2020).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Rosenzweig, R., Nillegoda, N. B., Mayer, M. P. & Bukau, B. The Hsp70 chaperone network. Nat. Rev. Mol. Cell Biol. 20, 665–680 (2019).

Article 
CAS 
PubMed 

Google Scholar
 

Kwak, P. B. & Tomari, Y. The N domain of Argonaute drives duplex unwinding during RISC assembly. Nat. Struct. Mol. Biol. 19, 145–151 (2012).

Article 
CAS 
PubMed 

Google Scholar
 

Pare, J. M., LaPointe, P. & Hobman, T. C. Hsp90 cochaperones p23 and FKBP4 physically interact with hAgo2 and activate RNA interference-mediated silencing in mammalian cells. Mol. Biol. Cell 24, 2303–2310 (2013).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Martinez, N. J., Chang, H.-M., Borrajo, J., de, R. & Gregory, R. I. The co-chaperones Fkbp4/5 control Argonaute2 expression and facilitate RISC assembly. RNA 19, 1583–1593 (2013).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Yamaguchi, S. et al. Structure of the Dicer-2–R2D2 heterodimer bound to a small RNA duplex. Nature 607, 393–398 (2022).

Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Broto, P., Moreau, G. & Vandycke, C. Molecular structures: perception, autocorrelation descriptor and sar studies. Perception of molecules: topological structure and 3-dimensional structure. European J. Med. Chem. 19, 61–65 (1984).

CAS 

Google Scholar
 

Prakash, T. P. et al. Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res. 42, 8796–8807 (2014).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Csermely, P. et al. ATP induces a conformational change of the 90-kDa heat shock protein (hsp90). J. Biol. Chem. 268, 1901–1907 (1993).

Article 
CAS 
PubMed 

Google Scholar
 

Punjani, A., Rubinstein, J. L., Fleet, D. J. & Brubaker, M. A. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat. Methods 14, 290–296 (2017).

Article 
CAS 
PubMed 

Google Scholar
 

Goddard, T. D. et al. UCSF ChimeraX: meeting modern challenges in visualization and analysis. Protein Sci. 27, 14–25 (2018).

Article 
CAS 
PubMed 

Google Scholar
 

Srivastava, D., Yadav, R. P., Singh, S., Boyd, K. & Artemyev, N. O. Unique interface and dynamics of the complex of HSP90 with a specialized cochaperone AIPL1. Structure 31, 309–317 (2023).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar
 

Lee, Y.-Y., Lee, H., Kim, H., Kim, V. N. & Roh, S.-H. Structure of the human DICER-pre-miRNA complex in a dicing state. Nature 615, 331–338 (2023).

Article 
ADS 
CAS 
PubMed 

Google Scholar
 

Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126–2132 (2004).

Article 
ADS 
PubMed 

Google Scholar
 

Liebschner, D. et al. Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr. D 75, 861–877 (2019).

Article 
ADS 
CAS 

Google Scholar