期刊
NUCLEIC ACIDS RESEARCH
卷 45, 期 6, 页码 3528-3536出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkw1171
关键词
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资金
- Cold Spring Harbor Laboratory Women in Science Award
- HHMI
Efficient gene silencing by RNA interference (RNAi) in vivo requires the recognition and binding of the 5'-phosphate of the guide strand of an siRNA by the Argonaute protein. However, for exogenous siRNAs it is limited by the rapid removal of the 5'-phosphate of the guide strand by metabolic enzymes. Here, we have determined the crystal structure of human Argonaute-2 in complex with the metabolically stable 5'-(E)-vinylphosphonate (5'-E-VP) guide RNA at 2.5-angstrom resolution. The structure demonstrates how the 5'binding site in the Mid domain of human Argonaute-2 is able to adjust the key residues in the 5'-nucleotide binding pocket to compensate for the change introduced by the modified nucleotide. This observation also explains improved binding affinity of the 5'-E-VP - modified siRNA to human Argonaute-2 in-vitro, as well as the enhanced silencing in the context of the trivalent N-acetylgalactosamine (GalNAc)conjugated siRNA in mice relative to the un-modified siRNA.
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