{"doi":"10.1101/2021.03.26.437253","title":"Norstictic acid is a selective allosteric transcriptional regulator","abstract":"Abstract Inhibitors of transcriptional protein-protein interactions (PPIs) have high value both as tools and for therapeutic applications. The PPI network mediated by the transcriptional coactivator Med25, for example, regulates stress-response and motility pathways and dysregulation of the PPI networks contributes to oncogenesis and metastasis. The canonical transcription factor binding sites within Med25 are large (~900 Å 2 ) and have little topology, and thus do not present an array of attractive small-molecule binding sites for inhibitor discovery. Here we demonstrate that the depsidone natural product norstictic acid functions through an alternative binding site to block Med25-transcriptional activator PPIs in vitro and in cell culture. Norstictic acid targets a binding site comprised of a highly dynamic loop flanking one canonical binding surface and in doing so, it both orthosterically and allosterically alters Med25-driven transcription in a patient-derived model of triple negative breast cancer. These results highlight the potential of Med25 as a therapeutic target as well as the inhibitor discovery opportunities presented by structurally dynamic loops within otherwise challenging proteins.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":223751,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.964,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":712219,"name":"Steven Sturlis","orcid":null,"position":1,"is_corresponding":false},{"id":712220,"name":"Paul A. Bruno","orcid":null,"position":2,"is_corresponding":false},{"id":289065,"name":"Joel A. Yates","orcid":"0000-0002-1462-8494","position":3,"is_corresponding":false},{"id":711331,"name":"Amanda L. Peiffer","orcid":"0000-0001-8113-9458","position":4,"is_corresponding":false},{"id":711332,"name":"Yejun Liu","orcid":"0000-0002-6398-7143","position":5,"is_corresponding":false},{"id":290420,"name":"Laura Goo","orcid":null,"position":6,"is_corresponding":false},{"id":491462,"name":"Liwei Bao","orcid":null,"position":7,"is_corresponding":false},{"id":712221,"name":"Samantha N. De Salle","orcid":null,"position":8,"is_corresponding":false},{"id":711333,"name":"Giselle Tamayo‐Castillo","orcid":"0000-0002-4912-8895","position":9,"is_corresponding":false},{"id":299321,"name":"Charles L. Brooks","orcid":"0000-0002-8149-5417","position":10,"is_corresponding":false},{"id":289066,"name":"Sofía D. Merajver","orcid":"0000-0002-6823-7130","position":11,"is_corresponding":false},{"id":292063,"name":"Anna K. Mapp","orcid":"0000-0003-0791-8327","position":12,"is_corresponding":false},{"id":472023,"name":"Julie M. Garlick","orcid":"0000-0001-8903-3471","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-18T23:54:14.760456Z","pmid":null,"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":[]}