21DX

Cryo-EM structure of the human P2X3 receptor in the ATP-bound, desensitized state

This is a non-PDB format compatible entry.

Summary for 21DX

• Entry DOI: 10.2210/pdb21dx/pdb
• EMDB information: 67603
• Descriptor: P2X purinoceptor 3, ADENOSINE-5'-TRIPHOSPHATE, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: p2x3, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 113835.96

Authors

Hattori, M.,Zhao, Z. (deposition date: 2025-12-09, release date: 2026-04-01, Last modification date: 2026-05-06)

Primary citation

Zhao, Z.,Wang, D.P.,Zhang, X.,Gao, Y.,Xu, H.,Teng, X.,Shen, C.,Chen, J.,Zhang, J.,Guo, C.R.,Hattori, M.
Structure of the human P2X3 receptor reveals the basis for subtype-selective inhibition by sivopixant.
Plos Biol., 24:e3003777-e3003777, 2026

PubMed Abstract: P2X receptors are ATP-gated cation channels, and the P2X3 subtype plays crucial roles in peripheral sensory neurons, including in chronic pain and chronic cough. Accordingly, P2X3 receptors have attracted substantial interest as a therapeutic target. Gefapixant, a negative allosteric modulator (NAM) of P2X3 receptors, has been approved in some countries for the treatment of chronic cough; however, its limited selectivity for P2X3 homomers over P2X2/P2X3 heteromers is associated with taste disturbance as a prominent adverse effect. These limitations have motivated the development of next-generation NAMs with improved subtype selectivity, but their subtype-specific allosteric inhibition mechanisms are unclear. Here, we report the cryo-EM structure of the human P2X3 receptor in complex with ATP and the P2X3-selective next-generation NAM sivopixant, an investigational drug. Sivopixant binds to an allosteric site at the portal of the central pocket in the extracellular domain, and structure-based mutational analysis by electrophysiology identifies key residues required for sivopixant-dependent inhibition of human P2X3 receptors. Structural comparisons across P2X subtypes, together with patch-clamp analyses of gain-of-function mutants that confer sensitivity to two investigational drugs, sivopixant and camlipixant, provided a broadly applicable structural framework for subtype selectivity. Furthermore, structural comparisons with apo and ATP-bound open states of P2X3 receptors, together with molecular dynamics simulations, revealed that sivopixant expands the upper-body domain to suppress the lower-body movements required for channel activation, thereby preventing channel opening even in the presence of ATP.

PubMed: 42018567
DOI: 10.1371/journal.pbio.3003777

Experimental method

ELECTRON MICROSCOPY (2.95 Å)