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@ARTICLE{Tanabe:856857,
      author       = {Tanabe, Koichi and Bonus, Michele and Tomiyama, Susumu and
                      Miyoshi, Kunji and Nagi, Minoru and Niimi, Kyoko and
                      Chindamporn, Ariya and Gohlke, Holger and Schmitt, Lutz and
                      Cannon, Richard D. and Niimi, Masakazu and Lamping, Erwin},
      title        = {{FK}506 resistance of {S}accharomyces cerevisiae {P}dr5 and
                      {C}andida albicans {C}dr1 involves mutations in the
                      transmembrane domains and extracellular loops},
      journal      = {Antimicrobial agents and chemotherapy},
      volume       = {63},
      number       = {1},
      issn         = {1098-6596},
      address      = {Washington, DC},
      publisher    = {Soc.},
      reportid     = {FZJ-2018-06196},
      pages        = {e01146-18},
      year         = {2019},
      abstract     = {The 23-membered-ring macrolide tacrolimus, a commonly used
                      immunosuppressant, also known as FK506, is a broad-spectrum
                      inhibitor and an efflux pump substrate of pleiotropic drug
                      resistance (PDR) ATP-binding cassette (ABC) transporters.
                      Little, however, is known about the molecular mechanism by
                      which FK506 inhibits PDR transporter drug efflux. Thus, to
                      obtain further insights we searched for FK506-resistant
                      mutants of Saccharomyces cerevisiae cells overexpressing
                      either the endogenous multidrug efflux pump, Pdr5, or its
                      Candida albicans orthologue, Cdr1. A simple, but powerful,
                      screen gave 69 FK506-resistant mutants with, between them,
                      72 mutations in either Pdr5 (37) or Cdr1 (35). Twenty
                      mutations were in just three Pdr5/Cdr1 equivalent amino acid
                      positions T550/T540 and T552/S542 of extracellular loop 1
                      (EL1) and A723/A713 of EL3. Sixty of the 72 mutations were
                      either in the ELs or the extracellular halves of individual
                      transmembrane spans (TMSs), while 11 mutations were found
                      near the centre of individual TMSs, mostly in predicted
                      TMS-TMS contact points, and only two mutations were in the
                      cytosolic nucleotide-binding domains of Pdr5. We propose
                      that FK506 inhibits Pdr5 and Cdr1 drug efflux by slowing
                      transporter opening and/or substrate release, and that
                      FK506-resistance of Pdr5/Cdr1 drug efflux is achieved by
                      modifying critical intramolecular contact points that, when
                      mutated, enable the co-transport of FK506 with other pump
                      substrates. This may also explain why the 35 Cdr1 mutations
                      that caused FK506-insensitivity of fluconazole efflux
                      differed from the 13 Cdr1 mutations that caused
                      FK506-insensitivity of cycloheximide efflux.},
      cin          = {JSC / ICS-6 / NIC},
      ddc          = {610},
      cid          = {I:(DE-Juel1)JSC-20090406 / I:(DE-Juel1)ICS-6-20110106 /
                      I:(DE-Juel1)NIC-20090406},
      pnm          = {511 - Computational Science and Mathematical Methods
                      (POF3-511) / Forschergruppe Gohlke $(hkf7_20170501)$},
      pid          = {G:(DE-HGF)POF3-511 / $G:(DE-Juel1)hkf7_20170501$},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30348662},
      UT           = {WOS:000454140200008},
      doi          = {10.1128/AAC.01146-18},
      url          = {https://juser.fz-juelich.de/record/856857},
}