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High-affinity agonism at the P2X7 receptor is mediated by three residues outside the orthosteric pocket

Author

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  • Adam C. Oken

    (Oregon Health & Science University)

  • Nicolas E. Lisi

    (Oregon Health & Science University)

  • Ipsita Krishnamurthy

    (Oregon Health & Science University)

  • Alanna E. McCarthy

    (Oregon Health & Science University)

  • Michael H. Godsey

    (Oregon Health & Science University)

  • Arthur Glasfeld

    (Oregon Health & Science University)

  • Steven E. Mansoor

    (Oregon Health & Science University
    Oregon Health & Science University)

Abstract

P2X receptors are trimeric ATP-gated ion channels that activate diverse signaling cascades. Due to its role in apoptotic pathways, selective activation of P2X7 is a potential experimental tool and therapeutic approach in cancer biology. However, mechanisms of high-affinity P2X7 activation have not been defined. We report high-resolution cryo-EM structures of wild-type rat P2X7 bound to the high-affinity agonist BzATP as well as significantly improved apo receptor structures in the presence and absence of sodium. Apo structures define molecular details of pore architecture and reveal how a partially hydrated Na+ ion interacts with the conductance pathway in the closed state. Structural, electrophysiological, and direct binding data of BzATP reveal that three residues just outside the orthosteric ATP-binding site are responsible for its high-affinity agonism. This work provides insights into high-affinity agonism for any P2X receptor and lays the groundwork for development of subtype-specific agonists applicable to cancer therapeutics.

Suggested Citation

  • Adam C. Oken & Nicolas E. Lisi & Ipsita Krishnamurthy & Alanna E. McCarthy & Michael H. Godsey & Arthur Glasfeld & Steven E. Mansoor, 2024. "High-affinity agonism at the P2X7 receptor is mediated by three residues outside the orthosteric pocket," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50771-6
    DOI: 10.1038/s41467-024-50771-6
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    References listed on IDEAS

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    2. Motoyuki Hattori & Eric Gouaux, 2012. "Molecular mechanism of ATP binding and ion channel activation in P2X receptors," Nature, Nature, vol. 485(7397), pages 207-212, May.
    3. Toshimitsu Kawate & Jennifer Carlisle Michel & William T. Birdsong & Eric Gouaux, 2009. "Crystal structure of the ATP-gated P2X4 ion channel in the closed state," Nature, Nature, vol. 460(7255), pages 592-598, July.
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    Cited by:

    1. Adam C. Oken & Nicolas E. Lisi & Ismayn A. Ditter & Haoyuan Shi & Nadia A. Nechiporuk & Steven E. Mansoor, 2024. "Cryo-EM structures of the human P2X1 receptor reveal subtype-specific architecture and antagonism by supramolecular ligand-binding," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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