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TitleStructure of the human P2X3 receptor reveals the basis for subtype-selective inhibition by sivopixant.
Journal, issue, pagesPLoS Biol, Vol. 24, Issue 4, Page e3003777, Year 2026
Publish dateApr 22, 2026
AuthorsZhixuan Zhao / Dong-Ping Wang / Xin Zhang / Yuan Gao / Hexin Xu / Xinyu Teng / Cheng Shen / Jirui Chen / Jinru Zhang / Chang-Run Guo / Motoyuki Hattori /
PubMed AbstractP2X 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 ...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.
External linksPLoS Biol / PubMed:42018567 / PubMed Central
MethodsEM (single particle)
Resolution2.95 - 3.34 Å
Structure data

67603

21dx

EMDB-67603, PDB-21dx:
Cryo-EM structure of the human P2X3 receptor in the ATP-bound, desensitized state
Method: EM (single particle) / Resolution: 2.95 Å

67624

21fg

EMDB-67624, PDB-21fg:
Cryo-EM structure of the human P2X3 receptor in the ATP- and sivopixant-bound closed state
Method: EM (single particle) / Resolution: 3.34 Å

Chemicals

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

PDB-1e2n:
HPT + HMTT

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / P2X3

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