Cryo-EM Study Maps Human AGO-HSP90-p23 Complex, Revealing 5′-Phosphate-Driven RISC Assembly
Updated
Updated · Nature.com · Jun 10
Cryo-EM Study Maps Human AGO-HSP90-p23 Complex, Revealing 5′-Phosphate-Driven RISC Assembly
2 articles · Updated · Nature.com · Jun 10
Summary
Researchers identified a human AGO-HSP90-p23 “AGO maturation complex” that holds Argonaute in an RNA-free state and can recreate de novo RISC assembly in vitro.
Cryo-EM showed AGO in a highly open conformation, with domains split across the HSP90 dimer to expose a positively charged cleft that accommodates a small-RNA duplex.
A duplex RNA carrying a 5′ terminal phosphate promoted AGO folding and loading, while single-stranded RNAs did not, indicating the duplex acts as a chaperone-like cofactor in assembly.
The work clarifies a long-unresolved step in RNA silencing and gives researchers a structural platform to test RNA features and chemical modifications for siRNA drug design.
Now we know how the 'gene hunter' protein gets its instructions, how will this help RNA drugs finally conquer diseases like Alzheimer's?
With the blueprint for gene silencing revealed, can we now design ultra-precise therapies that avoid all unintended side effects?
Molecular Mechanism of Argonaute Activation Discovered: Transforming RNA Drug Design and Accelerating a Booming $30B Therapeutics Market
Overview
A groundbreaking study by V. Narry Kim's team has revealed how Argonaute, a key protein in gene regulation, becomes active. Their research shows that microRNA acts as a crucial cofactor, guiding Argonaute’s proper folding and enabling its function. Without the right microRNA, Argonaute cannot achieve its active form, highlighting the direct role of RNA in protein folding. This discovery provides a detailed molecular blueprint, moving RNA drug design beyond trial-and-error and paving the way for more precise and effective RNA therapeutics.