Figure 6.

Replacing 2′-O-Methyl with 2′-Fluoro at Guide Strand Position 5 May Enhance siRNA-Target Interactions in the Seed

(A) Crystal structure of Ago2 loaded with a 21-mer unmodified siRNA guide strand (light magenta), optimally positioned to pair with its mRNA target (gray) in the seed (positions 2–8). (B) Image, as shown in (A), but also including a fully chemically modified 21-mer siRNA guide strand (black) with an alternating 2′-OMe/-F chemical pattern within its seed and 2′-OMe modification at position 5. Both siRNA sequences contain cysteine at guide strand position 5 (circled in red), but the chemically modified siRNA is positioned differently than the unmodified siRNA at this site, which may disrupt target binding.