The crystal structure of human Argonaute2.

Publication Type:

Journal Article

Authors:

Schirle, Nicole T; MacRae, Ian J

Source:

Science, Volume 336, Issue 6084, p.1037-40 (2012)

Keywords:

Amino Acid Sequence, Argonaute Proteins, Base Pairing, Binding Sites, Crystallography, X-Ray, Humans, Hydrogen Bonding, Hydrophobic and Hydrophilic Interactions, MicroRNAs, Models, Molecular, Molecular Sequence Data, Nucleic Acid Conformation, Protein Conformation, Protein Structure, Tertiary, RNA Interference, RNA, Guide, RNA, Messenger, Tryptophan

Abstract:

<p>Argonaute proteins form the functional core of the RNA-induced silencing complexes that mediate RNA silencing in eukaryotes. The 2.3 angstrom resolution crystal structure of human Argonaute2 (Ago2) reveals a bilobed 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 target messenger RNAs. Between nucleotides 6 and 7, there is a kink that may function in microRNA target recognition or release of sliced RNA products. Tandem tryptophan-binding pockets in the PIWI domain define a likely interaction surface for recruitment of glycine-tryptophan-182 (GW182) or other tryptophan-rich cofactors. These results will enable structure-based approaches for harnessing the untapped therapeutic potential of RNA silencing in humans.</p>