{"doi":"10.1073/pnas.2412653121","title":"Structure and function of\n                    <i>Mycobacterium tuberculosis</i>\n                    EfpA as a lipid transporter and its inhibition by BRD-8000.3","abstract":"<jats:p>\n                    EfpA, the first major facilitator superfamily (MFS) protein identified in\n                    <jats:italic>Mycobacterium tuberculosis</jats:italic>\n                    (Mtb), is an essential efflux pump implicated in resistance to multiple drugs. EfpA-inhibitors have been developed to kill drug-tolerant Mtb. However, the biological function of EfpA has not yet been elucidated. Here, we present the cryo-EM structures of EfpA complexed with lipids or the inhibitor BRD-8000.3 at resolutions of 2.9 Å and 3.4 Å, respectively. Unexpectedly, EfpA forms an antiparallel dimer. Functional studies reveal that EfpA is a lipid transporter and BRD-8000.3 inhibits its lipid transport activity. Intriguingly, the mutation V319F, known to confer resistance to BRD-8000.3, alters the expression level and oligomeric state of EfpA. Based on our results and the observation of other antiparallel dimers in the MFS family, we propose an antiparallel-function model of EfpA. Collectively, our work provides structural and functional insights into EfpA’s role in lipid transport and drug resistance, which would accelerate the development of antibiotics against this promising drug target.\n                  </jats:p>","journal":"Proceedings of the National Academy of Sciences","year":2024,"id":619549,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"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":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":270832,"name":"Xiaokang Zhang","orcid":"0000-0001-5073-2582","position":1,"is_corresponding":false},{"id":1598892,"name":"Yuanhang Yao","orcid":null,"position":2,"is_corresponding":false},{"id":31780,"name":"Xue Sun","orcid":"0000-0002-9716-7549","position":3,"is_corresponding":false},{"id":252742,"name":"Junqing Sun","orcid":null,"position":4,"is_corresponding":false},{"id":245744,"name":"Xiaomin Ma","orcid":"0009-0006-0458-5132","position":5,"is_corresponding":false},{"id":985496,"name":"Kai Yuan","orcid":"0000-0003-4113-8316","position":6,"is_corresponding":false},{"id":1598897,"name":"Guijie Bai","orcid":null,"position":7,"is_corresponding":false},{"id":1598898,"name":"Xuefei Pang","orcid":null,"position":8,"is_corresponding":false},{"id":1598899,"name":"Rongmao Hua","orcid":null,"position":9,"is_corresponding":false},{"id":1598900,"name":"Tianling Guo","orcid":null,"position":10,"is_corresponding":false},{"id":1598901,"name":"Yuqian Mi","orcid":null,"position":11,"is_corresponding":false},{"id":1075932,"name":"Lingzhi Wu","orcid":"0000-0002-0219-2056","position":12,"is_corresponding":false},{"id":322630,"name":"Jie Zhang","orcid":"0000-0002-9941-1568","position":13,"is_corresponding":false},{"id":830430,"name":"Yan Wu","orcid":"0000-0003-2734-0673","position":14,"is_corresponding":false},{"id":245747,"name":"Yingxia Liu","orcid":"0000-0001-6335-3346","position":15,"is_corresponding":false},{"id":1368359,"name":"Peiyi Wang","orcid":"0000-0001-7737-181X","position":16,"is_corresponding":false},{"id":40271,"name":"Catherine C. L. Wong","orcid":"0000-0002-6855-2798","position":17,"is_corresponding":false},{"id":598325,"name":"Xiaowei Chen","orcid":"0000-0001-6466-6248","position":18,"is_corresponding":false},{"id":1598905,"name":"Haixia Xiao","orcid":"0000-0003-0032-5430","position":19,"is_corresponding":false},{"id":6091,"name":"George F. Gao","orcid":"0000-0002-3869-615X","position":20,"is_corresponding":false},{"id":246439,"name":"Feng Gao","orcid":"0000-0002-7539-6455","position":21,"is_corresponding":false},{"id":1598891,"name":"Delin Li","orcid":"0000-0002-7967-1581","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Structure and function of\n                    <i>Mycobacterium tuberculosis</i>\n                    EfpA as a lipid transporter and its inhibition by BRD-8000.3","abstract":"<jats:p>\n                    EfpA, the first major facilitator superfamily (MFS) protein identified in\n                    <jats:italic>Mycobacterium tuberculosis</jats:italic>\n                    (Mtb), is an essential efflux pump implicated in resistance to multiple drugs. EfpA-inhibitors have been developed to kill drug-tolerant Mtb. However, the biological function of EfpA has not yet been elucidated. Here, we present the cryo-EM structures of EfpA complexed with lipids or the inhibitor BRD-8000.3 at resolutions of 2.9 Å and 3.4 Å, respectively. Unexpectedly, EfpA forms an antiparallel dimer. Functional studies reveal that EfpA is a lipid transporter and BRD-8000.3 inhibits its lipid transport activity. Intriguingly, the mutation V319F, known to confer resistance to BRD-8000.3, alters the expression level and oligomeric state of EfpA. Based on our results and the observation of other antiparallel dimers in the MFS family, we propose an antiparallel-function model of EfpA. Collectively, our work provides structural and functional insights into EfpA’s role in lipid transport and drug resistance, which would accelerate the development of antibiotics against this promising drug target.\n                  </jats:p>","is_dataset_classified":null,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"39441632","pmcid":"PMC11536138","openalex_id":"https://openalex.org/W4403681232","authors":[],"funders":[{"funder_name":"National Natural Science Foundation of China","grant_id":"82272379","title":null},{"funder_name":"National Key R&D Program of China","grant_id":"2020YFA0907","title":null},{"funder_name":"Tianjin Synthetic Biotechnology Innovation Capacity Improvement Project","grant_id":"TSBICIP-KJGG-014","title":null},{"funder_name":"Guangdong Basic and Applied Basic Research Foundation","grant_id":"2019A1515110675","title":null},{"funder_name":"China Postdoctoral Science Foundation","grant_id":"2019M660048","title":null}],"total_grants":5,"fwci":0.9189,"citation_percentile":0.74365771,"influential_citations":0,"citation_trend":[{"year":2025,"count":2},{"year":2026,"count":1}],"oa_status":"hybrid","license":"cc-by-nc-nd","oa_locations":[{"url":"https://doi.org/10.1073/pnas.2412653121","host_type":"journal"},{"url":"https://doi.org/10.1073/pnas.2412653121","host_type":"publisher"},{"url":"https://pnas.org/doi/pdf/10.1073/pnas.2412653121","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/39441632","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/11536138","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11536138/pdf/pnas.202412653.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC11536138","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC11536138?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Tuberculosis Research and Epidemiology","Antibiotic Resistance in Bacteria","Cancer therapeutics and mechanisms"],"mesh_terms":["Bacterial Proteins","Biological Transport","Models, Molecular","Mycobacterium tuberculosis","Cryoelectron Microscopy","Membrane Transport Proteins"],"keywords":["Major facilitator superfamily","Antiparallel (mathematics)","Efflux","Mycobacterium tuberculosis","Transporter","Function (biology)","Drug resistance","Biology","Chemistry","Biochemistry","Genetics","Tuberculosis","Gene","Medicine","Structural basis","Tb","Lipid Transporter","Efpa"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-03T07:33:51.881502Z","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":[]}