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The Crystal Structure of Human Argonaute2

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Science  26 Apr 2012:
1221551
DOI: 10.1126/science.1221551

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Abstract

Argonaute proteins form the functional core of the RNA-induced silencing complexes (RISCs) that mediate RNA silencing in eukaryotes. The 2.3-angstrom-resolution crystal structure of human Argonaute2 (Ago2) reveals a bi-lobed molecule with a central cleft for binding guide and target RNAs. Nucleotides 2 to 6 of a heterogeneous mixture of guide RNAs are positioned in an A-form conformation for base pairing with mRNA targets. Between nucleotides 6 and 7 there is a kink, which may function in miRNA target recognition or release of sliced RNA products. Tandem tryptophan binding pockets in the PIWI domain define a likely interaction surface for recruitment of GW182 or other tryptophan-rich cofactors. These results will enable structure-based approaches for harnessing the untapped therapeutic potential of RNA silencing in humans.

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