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@ARTICLE{Reiners:857537,
      author       = {Reiners, Melissa and Margreiter, Michael A. and
                      Oslender-Bujotzek, Adrienne and Rossetti, Giulia and
                      Gründer, Stefan and Schmidt, Axel},
      title        = {{T}he {C}onorfamide {RPRF}a {S}tabilizes the {O}pen
                      {C}onformation of {A}cid-{S}ensing {I}on {C}hannel 3 via the
                      {N}onproton {L}igand–{S}ensing {D}omain},
      journal      = {Molecular pharmacology},
      volume       = {94},
      number       = {4},
      issn         = {1521-0111},
      address      = {Bethesda, Md.},
      publisher    = {ASPET},
      reportid     = {FZJ-2018-06528},
      pages        = {1114 - 1124},
      year         = {2018},
      abstract     = {Acid-sensing ion channel 3 (ASIC3) is a proton-gated Na+
                      channel with important roles in pain. ASIC3 quickly
                      desensitizes in less than a second, limiting its capacity to
                      sense sustained acidosis during pain. RFamide neuropeptides
                      are modulators of ASIC3 that slow its desensitization and
                      induce a variable sustained current. The molecular mechanism
                      of slowed desensitization and the RFamide binding site on
                      ASIC3 are unknown. RPRFamide, a RFamide from the venom of a
                      cone snail, has a comparatively high affinity for ASIC3 and
                      strongly slows its desensitization. Here we show that
                      covalent binding of a UV-sensitive RPRFamide variant to
                      ASIC3 prevents desensitization, suggesting that RPRFamide
                      has to unbind from ASIC3 before it can desensitize.
                      Moreover, we show by in silico docking to a homology model
                      of ASIC3 that a cavity in the lower palm domain, which is
                      also known as the nonproton ligand–sensing domain, is a
                      potential binding site of RPRFamide. Finally, using
                      extensive mutagenesis of residues lining the nonproton
                      ligand–sensing domain, we confirm that this domain is
                      essential for RPRFamide modulation of ASIC3. As comparative
                      analysis of ASIC crystal structures in the open and in the
                      desensitized conformation suggests that the lower palm
                      domain contracts during desensitization, our results
                      collectively suggest that RPRFamide, and probably also other
                      RFamide neuropeptides, bind to the nonproton
                      ligand–sensing domain to stabilize the open conformation
                      of ASIC3.},
      cin          = {IAS-5 / INM-9 / JSC},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121 /
                      I:(DE-Juel1)JSC-20090406},
      pnm          = {574 - Theory, modelling and simulation (POF3-574) / 511 -
                      Computational Science and Mathematical Methods (POF3-511)},
      pid          = {G:(DE-HGF)POF3-574 / G:(DE-HGF)POF3-511},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30012583},
      UT           = {WOS:000445669700003},
      doi          = {10.1124/mol.118.112375},
      url          = {https://juser.fz-juelich.de/record/857537},
}