{"doi":"10.1074/jbc.m116.757153","title":"The role of transmembrane segment 5 (TM5) in Na2 release and the conformational transition of neurotransmitter:sodium symporters toward the inward-open state","abstract":null,"journal":"Journal of Biological Chemistry","year":2017,"id":640869,"datarank":0.515098080672772,"base_score":3.4339872044851463,"endowment":3.4339872044851463,"self_citation_contribution":0.515098080672772,"citation_network_contribution":0.0,"self_endowment_contribution":0.515098080672772,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":30,"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":367132,"name":"Zheng Li","orcid":"0000-0002-3188-8300","position":1,"is_corresponding":false},{"id":345799,"name":"Matthias Quick","orcid":"0000-0002-8620-827X","position":2,"is_corresponding":false},{"id":1665851,"name":"Lina Malinauskaite","orcid":null,"position":3,"is_corresponding":false},{"id":345804,"name":"Poul Nissen","orcid":"0000-0003-0948-6628","position":4,"is_corresponding":false},{"id":317550,"name":"Harel Weinstein","orcid":"0000-0003-3473-9818","position":5,"is_corresponding":false},{"id":307532,"name":"Jonathan A. Javitch","orcid":"0000-0001-7395-2967","position":6,"is_corresponding":false},{"id":228325,"name":"Lei Shi","orcid":"0000-0002-6043-8819","position":7,"is_corresponding":false},{"id":1446585,"name":"Sebastian Stolzenberg","orcid":"0000-0002-8900-6454","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"The role of transmembrane segment 5 (TM5) in Na2 release and the conformational transition of neurotransmitter:sodium symporters toward the inward-open state","abstract":"Neurotransmitter:sodium symporters (NSSs) terminate neurotransmission by the reuptake of released neurotransmitters. This active accumulation of substrate against its concentration gradient is driven by the transmembrane Na + gradient and requires that the transporter traverses several conformational states. LeuT, a prokaryotic NSS homolog, has been crystallized in outward-open, outward-occluded, and inward-open states. Two crystal structures of another prokaryotic NSS homolog, the multihydrophobic amino acid transporter (MhsT) from Bacillus halodurans , have been resolved in novel inward-occluded states, with the extracellular vestibule closed and the intracellular portion of transmembrane segment 5 (TM5i) in either an unwound or a helical conformation. We have investigated the potential involvement of TM5i in binding and unbinding of Na2, i.e. the Na + bound in the Na2 site, by carrying out comparative molecular dynamics simulations of the models derived from the two MhsT structures. We find that the helical TM5i conformation is associated with a higher propensity for Na2 release, which leads to the repositioning of the N terminus and transition to an inward-open state. By using comparative interaction network analysis, we also identify allosteric pathways connecting TM5i and the Na2 binding site to the extracellular and intracellular regions. Based on our combined computational and mutagenesis studies of MhsT and LeuT, we propose that TM5i plays a key role in Na2 binding and release associated with the conformational transition toward the inward-open state, a role that is likely to be shared across the NSS family.","is_dataset_classified":null,"base_score":3.4339872044851463,"endowment":3.4339872044851463,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"28320858","pmcid":"PMC5418039","openalex_id":"https://openalex.org/W2600839259","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"DA023694","title":null},{"funder_name":"National Institutes of Health","grant_id":"DA012408","title":null},{"funder_name":"National Institutes of Health","grant_id":"DA022413","title":null},{"funder_name":"National Institutes of Health","grant_id":"DA17293","title":null},{"funder_name":"National Institutes of Health","grant_id":"U54GM087519","title":null},{"funder_name":"NIDA NIH HHS","grant_id":"R01 DA017293","title":null},{"funder_name":"NIDA NIH HHS","grant_id":"K99 DA023694","title":null},{"funder_name":"Lundbeck Foundation","grant_id":"R126-2012-12576","title":null},{"funder_name":"NIDA NIH HHS","grant_id":"P01 DA012408","title":null},{"funder_name":"NIDA NIH HHS","grant_id":"K05 DA022413","title":null},{"funder_name":"NIDA NIH HHS","grant_id":"R00 DA023694","title":null}],"total_grants":11,"fwci":1.7231,"citation_percentile":0.84324511,"influential_citations":0,"citation_trend":[{"year":2018,"count":6},{"year":2019,"count":9},{"year":2020,"count":2},{"year":2021,"count":2},{"year":2022,"count":5},{"year":2023,"count":1},{"year":2024,"count":4},{"year":2025,"count":1}],"oa_status":"hybrid","license":"cc-by","oa_locations":[{"url":"http://www.jbc.org/article/S0021925820428510/pdf","host_type":"journal"},{"url":"http://www.jbc.org/article/S0021925820428510/pdf","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0021925820428510?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0021925820428510?httpAccept=text/plain","host_type":"publisher"},{"url":"https://syndication.highwire.org/content/doi/10.1074/jbc.M116.757153","host_type":"publisher"},{"url":"https://doi.org/10.1074/jbc.m116.757153","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/28320858","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/5418039","host_type":"repository"},{"url":"https://pure.au.dk/portal/en/publications/d0fbb373-6c78-4109-b78e-855df10ff049","host_type":""}],"fields_of_study":["Ion channel regulation and function","Neuroscience and Neuropharmacology Research","Cellular transport and secretion"],"mesh_terms":["Protein Domains","Allosteric Regulation","Bacillus","Bacterial Proteins","Sodium","Amino Acid Transport Systems","Plasma Membrane Neurotransmitter Transport Proteins","Molecular Dynamics Simulation"],"keywords":["Symporter","Chemistry","Transmembrane domain","Neurotransmitter transporter","Allosteric regulation","Biophysics","Reuptake","Conformational change","Transmembrane protein","Synaptic cleft","Binding site","Transporter","Extracellular","Stereochemistry","Neurotransmitter","Biochemistry","Amino acid","Biology","Enzyme","Molecular dynamics","Neurotransmitter Transport","Amino Acid Transport","Metal Ion-protein Interaction"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"pdb"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-07T14:16:33.765970Z","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":[]}