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PDBsum entry 5js1
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Hydrolase/RNA
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PDB id
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5js1
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References listed in PDB file
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Key reference
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Title
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Structural analysis of human argonaute-2 bound to a modified sirna guide.
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Authors
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N.T.Schirle,
G.A.Kinberger,
H.F.Murray,
W.F.Lima,
T.P.Prakash,
I.J.Macrae.
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Ref.
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J Am Chem Soc, 2016,
138,
8694-8697.
[DOI no: ]
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PubMed id
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Abstract
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Incorporation of chemical modifications into small interfering RNAs (siRNAs)
increases their metabolic stability and improves their tissue distribution.
However, how these modifications impact interactions with Argonaute-2 (Ago2),
the molecular target of siRNAs, is not known. Herein we present the crystal
structure of human Ago2 bound to a metabolically stable siRNA containing
extensive backbone modifications. Comparison to the structure of an equivalent
unmodified-siRNA complex indicates that the structure of Ago2 is relatively
unaffected by chemical modifications in the bound siRNA. In contrast, the
modified siRNA appears to be much more plastic and shifts, relative to the
unmodified siRNA, to optimize contacts with Ago2. Structure-activity analysis
reveals that even major conformational perturbations in the 3' half of the siRNA
seed region have a relatively modest effect on knockdown potency. These findings
provide an explanation for a variety of modification patterns tolerated in
siRNAs and a structural basis for advancing therapeutic siRNA design.
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