{"doi":"10.1101/2020.03.05.978833","title":"<i>Mycobacterium tuberculosis</i> FasR senses long fatty acyl-CoA through a tunnel, inducing DNA-dissociation via a transmission spine","abstract":"ABSTRACT Mycobacterium tuberculosis is a pathogen with a unique cell envelope including very long fatty acids, implicated in bacterial resistance and host immune modulation. FasR is a two-domain transcriptional activator that belongs to the TetR family of regulators, and plays a central role in mycobacterial long-chain fatty acyl-CoA sensing and lipid biosynthesis regulation. We now disclose crystal structures of M. tuberculosis FasR in complex with acyl effector ligands and with DNA, uncovering its sensory and switching mechanisms. A long tunnel traverses the entire effector-binding domain, enabling long fatty acyl effectors to bind. Only when the tunnel is entirely occupied, the protein dimer adopts a rigid configuration, with its DNA-binding domains in an open state that leads to DNA dissociation. Structure-guided point-mutations further support this effector-dependent mechanism. The protein-folding hydrophobic core, connecting the two domains, is completed by the effector ligand into a continuous spine, explaining the allosteric flexible-to-ordered transition. The transmission spine is conserved in all TetR-like transcription factors, offering new opportunities for anti-tuberculosis drug discovery.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":126354,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":396994,"name":"Lautaro Diacovich","orcid":"0000-0002-3339-0100","position":1,"is_corresponding":false},{"id":339039,"name":"Felipe Trajtenberg","orcid":"0000-0003-0427-5549","position":2,"is_corresponding":false},{"id":396995,"name":"N. Larrieux","orcid":"0000-0002-8027-9544","position":3,"is_corresponding":false},{"id":396996,"name":"Emilio L. Malchiodi","orcid":"0000-0001-7501-3330","position":4,"is_corresponding":false},{"id":396997,"name":"Marisa M. Fernández","orcid":"0000-0002-7480-5907","position":5,"is_corresponding":false},{"id":396998,"name":"Gabriela Gago","orcid":"0000-0001-7668-0119","position":6,"is_corresponding":false},{"id":398502,"name":"Hugo Gramajo","orcid":null,"position":7,"is_corresponding":false},{"id":339045,"name":"Alejandro Buschiazzo","orcid":"0000-0002-2509-6526","position":8,"is_corresponding":false},{"id":398501,"name":"Julia Lara","orcid":null,"position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":null,"created_at":"2026-07-18T23:15:23.509897Z","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":[]}