{"doi":"10.1093/nar/gkac897","title":"ADAR activation by inducing a <i>syn</i> conformation at guanosine adjacent to an editing site","abstract":"ADARs (adenosine deaminases acting on RNA) can be directed to sites in the transcriptome by complementary guide strands allowing for the correction of disease-causing mutations at the RNA level. However, ADARs show bias against editing adenosines with a guanosine 5' nearest neighbor (5'-GA sites), limiting the scope of this approach. Earlier studies suggested this effect arises from a clash in the RNA minor groove involving the 2-amino group of the guanosine adjacent to an editing site. Here we show that nucleosides capable of pairing with guanosine in a syn conformation enhance editing for 5'-GA sites. We describe the crystal structure of a fragment of human ADAR2 bound to RNA bearing a G:G pair adjacent to an editing site. The two guanosines form a Gsyn:Ganti pair solving the steric problem by flipping the 2-amino group of the guanosine adjacent to the editing site into the major groove. Also, duplexes with 2'-deoxyadenosine and 3-deaza-2'-deoxyadenosine displayed increased editing efficiency, suggesting the formation of a Gsyn:AH+anti pair. This was supported by X-ray crystallography of an ADAR complex with RNA bearing a G:3-deaza dA pair. This study shows how non-Watson-Crick pairing in duplex RNA can facilitate ADAR editing enabling the design of next generation guide strands for therapeutic RNA editing.","journal":"Nucleic Acids Research","year":2022,"id":247297,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":34,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.954,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":504309,"name":"Agya Karki","orcid":"0009-0002-4845-4821","position":1,"is_corresponding":false},{"id":694152,"name":"Xander E. Wilcox","orcid":"0000-0003-3941-5222","position":2,"is_corresponding":false},{"id":884765,"name":"Herra G. Mendoza","orcid":"0000-0003-3151-9772","position":3,"is_corresponding":false},{"id":884766,"name":"Aashrita Manjunath","orcid":"0009-0007-9999-6176","position":4,"is_corresponding":false},{"id":884767,"name":"Victorio Jauregui Matos","orcid":"0000-0003-2009-5521","position":5,"is_corresponding":false},{"id":249825,"name":"Andrew J. Fisher","orcid":"0000-0003-3488-6594","position":6,"is_corresponding":false},{"id":245813,"name":"Peter A. Beal","orcid":"0000-0003-4855-7185","position":7,"is_corresponding":false},{"id":504306,"name":"Erin Doherty","orcid":"0000-0002-1555-4124","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T00:23:53.369530Z","pmid":"36243986","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}