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@ARTICLE{Gabriel:614019,
      author       = {Gabriel, Florian and Spriestersbach, Lea and Fuhrmann,
                      Antonia and Jungnickel, Katharina and Mostafavi, Siavash and
                      Pardon, Els and Steyaert, Jan and Loew, Christian},
      title        = {{S}tructural basis of substrate transport and drug
                      recognition by the human thiamine transporter {SLC}19{A}3},
      reportid     = {PUBDB-2024-05720},
      year         = {2024},
      abstract     = {Thiamine (vitamin B1) functions as an essential coenzyme in
                      cells. Humans and other mammals cannot synthesise this
                      vitamin de novo and thus have to take it up from their diet.
                      Eventually, every cell needs to import thiamine across its
                      plasma membrane which is mainly mediated by two specific
                      thiamine transporters SLC19A2 and SLC19A3. Loss of function
                      mutations in either of these transporters leads to
                      detrimental, life-threatening metabolic disorders. SLC19A3
                      is furthermore a major site of drug interactions. Many
                      medications, including antidepressants, antibiotics and
                      chemotherapeutics are known to inhibit this transporter,
                      with potentially fatal consequences for patients. Despite a
                      thorough functional characterisation over the past two
                      decades, the structural basis of its transport mechanism and
                      drug interactions has remained elusive. Here, we report
                      eight cryo-electron microscopy (cryo-EM) structures of the
                      human thiamine transporter SLC19A3 in complex with various
                      ligands. Conformation-specific nanobodies enabled us to
                      capture different states of SLC19A3’s transport cycle,
                      revealing the molecular details of thiamine recognition and
                      transport. We identified nine novel drug interactions of
                      SLC19A3 and determined structures of the transporter in
                      complex with the inhibitors fedratinib, hydroxychloroquine,
                      amprolium and amitriptyline. These data allow us to develop
                      an understanding of the transport mechanism and ligand
                      recognition of SLC19A3.},
      cin          = {CSSB-EMBL-CL},
      cid          = {I:(DE-H253)CSSB-EMBL-CL-20210806},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      experiment   = {EXP:(DE-MLZ)NOSPEC-20140101},
      typ          = {PUB:(DE-HGF)25},
      doi          = {10.1101/2024.03.11.584396},
      url          = {https://bib-pubdb1.desy.de/record/614019},
}