Molecular mechanisms of human P2X3 receptor channel activation and modulation by divalent cation bound ATP.

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  • Additional Information
    • Source:
      Publisher: eLife Sciences Publications, Ltd Country of Publication: England NLM ID: 101579614 Publication Model: Electronic Cited Medium: Internet ISSN: 2050-084X (Electronic) Linking ISSN: 2050084X NLM ISO Abbreviation: Elife Subsets: MEDLINE
    • Publication Information:
      Original Publication: Cambridge, UK : eLife Sciences Publications, Ltd., 2012-
    • Subject Terms:
      Adenosine Triphosphate/*metabolism ; Calcium/*metabolism ; Cations, Divalent/*metabolism ; Magnesium/*metabolism ; Receptors, Purinergic P2X3/*chemistry ; Receptors, Purinergic P2X3/*metabolism; Binding Sites ; Humans ; Protein Binding ; Protein Conformation
    • Abstract:
      P2X3 receptor channels expressed in sensory neurons are activated by extracellular ATP and serve important roles in nociception and sensory hypersensitization, making them attractive therapeutic targets. Although several P2X3 structures are known, it is unclear how physiologically abundant Ca 2+ -ATP and Mg 2+ -ATP activate the receptor, or how divalent cations regulate channel function. We used structural, computational and functional approaches to show that a crucial acidic chamber near the nucleotide-binding pocket in human P2X3 receptors accommodates divalent ions in two distinct modes in the absence and presence of nucleotide. The unusual engagement between the receptor, divalent ion and the γ-phosphate of ATP enables channel activation by ATP-divalent complex, cooperatively stabilizes the nucleotide on the receptor to slow ATP unbinding and recovery from desensitization, a key mechanism for limiting channel activity. These findings reveal how P2X3 receptors recognize and are activated by divalent-bound ATP, aiding future physiological investigations and drug development.
      Competing Interests: ML, YW, RB, FM, SS, MH No competing interests declared, JF, KS Reviewing editor, eLife
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    • Contributed Indexing:
      Keywords: Ca binding sites; Mg binding sites; Mg-ATP; divalent cations; forms of ATP; human; molecular biophysics; structural biology
    • Molecular Sequence:
      PDB 6AH5
    • Accession Number:
      0 (Cations, Divalent)
      0 (Receptors, Purinergic P2X3)
      8L70Q75FXE (Adenosine Triphosphate)
      I38ZP9992A (Magnesium)
      SY7Q814VUP (Calcium)
    • Publication Date:
      Date Created: 20190625 Date Completed: 20200225 Latest Revision: 20200309
    • Publication Date:
      20240829
    • Accession Number:
      PMC6590987
    • Accession Number:
      10.7554/eLife.47060
    • Accession Number:
      31232692