ADARs (adenosine deaminases acting on RNA) are editing enzymes that convert adenosine (A) to inosine (I) in duplex RNA, a modification that has wide-ranging consequences on RNA function including changing the meaning of specific codons in mRNA, altering miRNA recognition sites and redirecting RNA splicing.  Recent work has demonstrated a causal link between altered RNA editing and human disease.  However, our understanding of the ADAR reaction mechanism, origin of editing site selectivity and the effect of disease-causing mutations has been limited by the lack of high-resolution structural data for complexes of ADARs bound to RNA.  This presentation will describe the combined chemical biology/structural biology approach used to solve this problem wherein RNA bearing a nucleoside analog was used to trap the reaction intermediate allowing for crystallization of the resulting complexes. Solving the structures of these complexes has uncovered several important features of ADAR-substrate recognition and the ADAR reaction mechanism.  In addition, our studies have provided new insight for the design of reagents capable of directing ADARs to “repair” G-to-A mutations present in disease-associated transcripts.<br/>

RNA Editing by Adenosine Deaminases that act on RNA

ACS Fall 2020 Virtual Meeting

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