The prospects are improving for more precise design of ribonucleic acid (RNA) therapeutics to treat intractable diseases caused by gene overexpression, following the elucidation of the formation process of proteins that regulate gene expression.

The Ministry of Science and ICT announced on the 11th that a joint research team led by Kim V. Narry, director of the RNA Research Center at the Institute for Basic Science (IBS) and distinguished professor at Seoul National University, and Professor Noh Sung-hoon of the School of Biological Sciences at Seoul National University has, for the first time worldwide, identified the assembly process of “Argonaute,” a protein that regulates gene expression, and published the results in the international journal Nature.

Within cells, microRNAs (miRNAs) exist to suppress excessive gene expression. miRNAs bind to Argonaute to form a “protein-RNA complex,” thereby regulating gene expression. Until now, the process by which Argonaute binds to miRNA and becomes activated had not been clarified.

To observe the activation process, the research team for the first time isolated and purified an Argonaute complex bound to chaperones and analyzed the structure of the complex using cryo-electron microscopy. Chaperones are proteins that assist in the structural formation of Argonaute.

The analysis found that chaperones hold Argonaute in an “open conformation,” creating space for miRNA to enter. When miRNA enters and binds in this open space, the chaperones dissociate and Argonaute switches to a “closed conformation.” When the research team reconstructed the Argonaute assembly process in vitro, the Argonaute complex precisely executed the function of cleaving target genes.

The research team also identified the conditions for RNA to be efficiently loaded onto Argonaute and examined how the chemical moieties (chemical fragments attached to the RNA backbone) of next-generation drug platform “small interfering RNA (siRNA)” therapeutics affect Argonaute assembly, thereby enhancing the efficiency and applicability of RNA therapeutic design.

Kim stated, “We have provided a molecular and theoretical basis for RNA therapeutic design, which until now has depended on trial and error,” adding, “This is expected to enable the development of more efficient and safer therapeutics in the future.”

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