High-affinity agonism at the P2X 7 receptor is mediated by three residues outside the orthosteric pocket.

Autor: Oken AC; Department of Chemical Physiology & Biochemistry, Oregon Health & Science University, Portland, OR, 97239, USA., Lisi NE; Department of Chemical Physiology & Biochemistry, Oregon Health & Science University, Portland, OR, 97239, USA., Krishnamurthy I; Department of Chemical Physiology & Biochemistry, Oregon Health & Science University, Portland, OR, 97239, USA., McCarthy AE; Division of Cardiovascular Medicine, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, 97239, USA., Godsey MH; Department of Chemical Physiology & Biochemistry, Oregon Health & Science University, Portland, OR, 97239, USA., Glasfeld A; Department of Chemical Physiology & Biochemistry, Oregon Health & Science University, Portland, OR, 97239, USA., Mansoor SE; Department of Chemical Physiology & Biochemistry, Oregon Health & Science University, Portland, OR, 97239, USA. mansoors@ohsu.edu.; Division of Cardiovascular Medicine, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, 97239, USA. mansoors@ohsu.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 06; Vol. 15 (1), pp. 6662. Date of Electronic Publication: 2024 Aug 06.
DOI: 10.1038/s41467-024-50771-6
Abstrakt: P2X receptors are trimeric ATP-gated ion channels that activate diverse signaling cascades. Due to its role in apoptotic pathways, selective activation of P2X 7 is a potential experimental tool and therapeutic approach in cancer biology. However, mechanisms of high-affinity P2X 7 activation have not been defined. We report high-resolution cryo-EM structures of wild-type rat P2X 7 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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