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@ARTICLE{OrtegaRamrez:1037779,
      author       = {Ortega-Ramírez, Audrey Magdalena and Albani, Simone and
                      Bachmann, Michèle and Schmidt, Axel and Pinoé-Schmidt,
                      Manuela and Assmann, Marc and Augustinowski, Katrin and
                      Rossetti, Giulia and Gründer, Stefan},
      title        = {{A} conserved peptide-binding pocket in {H}y{N}a{C}/{ASIC}
                      ion channels},
      journal      = {Proceedings of the National Academy of Sciences of the
                      United States of America},
      volume       = {121},
      number       = {41},
      issn         = {0027-8424},
      address      = {Washington, DC},
      publisher    = {National Acad. of Sciences},
      reportid     = {FZJ-2025-00931},
      pages        = {e2409097121},
      year         = {2024},
      abstract     = {The only known peptide-gated ion channels—FaNaCs/WaNaCs
                      and HyNaCs—belong to different clades of the DEG/ENaC
                      family. FaNaCs are activated by the short neuropeptide
                      FMRFamide, and HyNaCs by Hydra RFamides, which are not
                      evolutionarily related to FMRFamide. The FMRFamide-binding
                      site in FaNaCs was recently identified in a cleft atop the
                      large extracellular domain. However, this cleft is not
                      conserved in HyNaCs. Here, we combined molecular modeling
                      and site-directed mutagenesis and identified a putative
                      binding pocket for Hydra-RFamides in the extracellular
                      domain of the heterotrimeric HyNaC2/3/5. This pocket
                      localizes to only one of the three subunit interfaces,
                      indicating that this trimeric ion channel binds a single
                      peptide ligand. We engineered an unnatural amino acid at the
                      putative binding pocket entrance, which allowed covalent
                      tethering of Hydra RFamide to the channel, thereby trapping
                      the channel in an open conformation. The identified pocket
                      localizes to the same region as the acidic pocket of
                      acid-sensing ion channels (ASICs), which binds peptide
                      ligands. The pocket in HyNaCs is less acidic, and both
                      electrostatic and hydrophobic interactions contribute to
                      peptide binding. Collectively, our results reveal a
                      conserved ligand-binding pocket in HyNaCs and ASICs and
                      indicate independent evolution of peptide-binding cavities
                      in the two subgroups of peptide-gated ion channels.},
      cin          = {INM-9 / IAS-5},
      ddc          = {500},
      cid          = {I:(DE-Juel1)INM-9-20140121 / I:(DE-Juel1)IAS-5-20120330},
      pnm          = {5252 - Brain Dysfunction and Plasticity (POF4-525)},
      pid          = {G:(DE-HGF)POF4-5252},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {39365813},
      UT           = {WOS:001352155400008},
      doi          = {10.1073/pnas.2409097121},
      url          = {https://juser.fz-juelich.de/record/1037779},
}