{"doi":"10.1021/jacs.2c11483","title":"Radical Transport Facilitated by a Proton Transfer Network at the Subunit Interface of Ribonucleotide Reductase","abstract":"Ribonucleotide reductases (RNRs) play an essential role in the conversion of nucleotides to deoxynucleotides in all organisms. The Escherichia coli class Ia RNR requires two homodimeric subunits, α and β. The active form is an asymmetric αα′ββ′ complex. The α subunit houses the site for nucleotide reduction initiated by a thiyl radical (C 439 •), and the β subunit houses the diferric-tyrosyl radical (Y 122 •) that is essential for C 439 • formation. The reactions require a highly regulated and reversible long-range proton-coupled electron transfer pathway involving Y 122 •[β] ↔ W 48?[β] ↔ Y 356 [β] ↔ Y 731 [α] ↔ Y 730 [α] ↔ C 439 [α]. In a recent cryo-EM structure, Y 356 [β] was revealed for the first time and it, along with Y 731 [α], spans the asymmetric α/β interface. An E 52 [β] residue, which is essential for Y 356 oxidation, allows access to the interface and resides at the head of a polar region comprising R 331 [α], E 326 [α], and E 326 [α′] residues. Mutagenesis studies with canonical and unnatural amino acid substitutions now suggest that these ionizable residues are important in enzyme activity. To gain further insights into the roles of these residues, Y 356 • was photochemically generated using a photosensitizer covalently attached adjacent to Y 356 [β]. Mutagenesis studies, transient absorption spectroscopy, and photochemical assays monitoring deoxynucleotide formation collectively indicate that the E 52 [β], R 331 [α], E 326 [α], and E 326 [α′] network plays the essential role of shuttling protons associated with Y 356 oxidation from the interface to bulk solvent.","journal":"Journal of the American Chemical Society","year":2023,"id":363573,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1118016,"name":"David Song","orcid":"0000-0002-3560-0300","position":1,"is_corresponding":false},{"id":241330,"name":"Catherine L. Drennan","orcid":"0000-0001-5486-2755","position":2,"is_corresponding":false},{"id":262762,"name":"JoAnne Stubbe","orcid":"0000-0001-8076-4489","position":3,"is_corresponding":false},{"id":34935,"name":"Daniel G. Nocera","orcid":"0000-0001-5055-320X","position":4,"is_corresponding":false},{"id":241328,"name":"Chang Cui","orcid":"0000-0002-4709-7458","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T01:14:32.510714Z","pmid":"36812162","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":[]}