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

Adam C. Oken, Nicolas E. Lisi, Ipsita Krishnamurthy, Alanna E. McCarthy, Michael H. Godsey, Arthur Glasfeld and Steven E. Mansoor ()
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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

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50771-6

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