Journal
STRUCTURE
Volume 23, Issue 5, Pages 851-862Publisher
CELL PRESS
DOI: 10.1016/j.str.2015.03.012
Keywords
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Funding
- Hannover Biomedical Research School (HBRS)
- Hannover Medical School
- Program of RAS on Molecular and Cellular Biology
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2'-5'-Oligoadenylate synthetases (OASs) produce the second messenger 2'-5'-oligoadenylate, which activates RNase L to induce an intrinsic antiviral state. We report on the crystal structures of catalytic intermediates of OAS1 including the OAS1.dsRNA complex without substrates, with a donor substrate, and with both donor and acceptor substrates. Combined with kinetic studies of point mutants and the previously published structure of the apo form of OAS1, the new data suggest a sequential mechanism of OAS activation and show the individual roles of each component. They reveal a dsRNA-mediated push-pull effect responsible for large conformational changes in OAS1, the catalytic role of the active site Mg2+, and the structural basis for the 2'-specificity of product formation. Our data reveal similarities and differences in the activation mechanisms of members of the OAS/cyclic GMP-AMP synthase family of innate immune sensors. In particular, they show how helix 3(10)3-alpha 5 blocks the synthesis of cyclic dinucleotides by OAS1.
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