8V4S

Cryo-EM structure of the rat P2X7 receptor in the apo closed state purified in the absence of sodium

Summary for 8V4S

• Entry DOI: 10.2210/pdb8v4s/pdb
• Related: 8TR5 8TRJ
• EMDB information: 41570 41581 42976
• Descriptor: P2X purinoceptor 7, GUANOSINE-5'-DIPHOSPHATE, ZINC ION, ... (6 entities in total)
• Functional Keywords: membrane protein, ion channel, ligand-gate ion channel, p2x receptor, allosteric antagonist, high-affinity agonist
• Biological source: Rattus; More
• Total number of polymer chains: 3
• Total formula weight: 212976.67

Authors

Oken, A.C.,Lisi, N.E.,Krishnamurthy, I.,McCarthy, A.E.,Godsey, M.H.,Glasfeld, A.,Mansoor, S.E. (deposition date: 2023-11-29, release date: 2024-08-14, Last modification date: 2024-11-20)

Primary citation

Oken, A.C.,Lisi, N.E.,Krishnamurthy, I.,McCarthy, A.E.,Godsey, M.H.,Glasfeld, A.,Mansoor, S.E.
High-affinity agonism at the P2X 7 receptor is mediated by three residues outside the orthosteric pocket.
Nat Commun, 15:6662-6662, 2024

PubMed Abstract: P2X receptors are trimeric ATP-gated ion channels that activate diverse signaling cascades. Due to its role in apoptotic pathways, selective activation of P2X is a potential experimental tool and therapeutic approach in cancer biology. However, mechanisms of high-affinity P2X activation have not been defined. We report high-resolution cryo-EM structures of wild-type rat P2X 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.

PubMed: 39107314
DOI: 10.1038/s41467-024-50771-6

Experimental method

ELECTRON MICROSCOPY (2.49 Å)