{"doi":"10.1002/cbic.202400709","title":"Photoactivatable O‐GlcNAc Transferase Library Enables Covalent Chemical Capture of Solvent‐Exposed TPR Domain Interactions","abstract":"O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) is an essential, stress-sensing enzyme responsible for adding the O-GlcNAc monosaccharide to thousands of nuclear and cytoplasmic proteins to regulate cellular homeostasis. OGT substrates are found in almost all intracellular processes, and perturbations in protein O-GlcNAc levels have been implicated in proteostatic diseases, such as cancers, metabolic disorders, and neurodegeneration. This broad disease activity makes OGT an attractive therapeutic target; however, the substrate diversity makes pan-inhibition as a therapeutic strategy unfeasible. Rather, a substrate-specific approach to targeting is more advantageous, but how OGT chooses its substrates remains poorly understood. Substrate specificity is controlled by the interactions between OGT's non-catalytic tetratricopeptide repeat (TPR) domain, rather than its glycosyltransferase domain. OGT's TPR domain forms a 100 Å superhelical structure, containing a lumenal surface, known as the substrate-binding surface, and a solvent-exposed surface. To date, there are no tools to site-selectively target regions of the domain and differentiate between the two binding surfaces. Here, we developed a library of recombinant OGT constructs containing site-specifically incorporated photoactivatable unnatural amino acids (UAAs) along the solvent-exposed surface of the TPR domain to covalently capture and map OGT's interactome.","journal":"ChemBioChem","year":2024,"id":451957,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9593,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1273838,"name":"Tiarra J. Glogowski","orcid":null,"position":1,"is_corresponding":false},{"id":1273357,"name":"Erin NewRingeisen","orcid":"0000-0001-5285-3062","position":2,"is_corresponding":false},{"id":1273358,"name":"Huy V. Huynh","orcid":"0009-0007-9304-8087","position":3,"is_corresponding":false},{"id":1273839,"name":"Melanie G. Roberts","orcid":null,"position":4,"is_corresponding":false},{"id":1273840,"name":"Madison M. Rognerud","orcid":null,"position":5,"is_corresponding":false},{"id":1273841,"name":"Hahns E. Huebsch","orcid":null,"position":6,"is_corresponding":false},{"id":563337,"name":"Cassandra M. Joiner","orcid":"0000-0003-0476-9418","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-19T02:02:45.951080Z","pmid":"39541256","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":[]}