Structure of the human P2X3 receptor reveals the basis for subtype-selective inhibition by sivopixant.

Overview

Authors: Zhixuan Zhao¹, Dong-Ping Wang², Xin Zhang², Yuan Gao², Hexin Xu¹, Xinyu Teng¹, Cheng Shen¹, Jirui Chen¹, Jinru Zhang³, Chang-Run Guo², Motoyuki Hattori¹

ORCID iDs: Motoyuki Hattori

State Key Laboratory of Genetics and Development of Complex Phenotypes, Collaborative Innovation Center of Genetics and Development, Department of Physiology and Neurobiology, School of Life Sciences, Fudan University, Shanghai, China
State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
State Key Laboratory of Genetics and Development of Complex Phenotypes, Department of Biochemistry and Biophysics, School of Life Sciences, Fudan University, Shanghai, China

Institutions: Fudan University (China); China Pharmaceutical University (China); State Key Laboratory of Natural Medicine

Journal: PLoS biology, volume 24, issue 4, article e3003777

Dates: received 29 January 2026; accepted 9 April 2026; published online 22 April 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1371/journal.pbio.3003777 · PMID 42018567 · PMCID PMC13132459 · OpenAlex W7155173822

Open access: gold, a free copy (OpenAlex)

Status: data only

Categories: histology / microscopy (modality), human (organism), cellular / molecular (subfield)

Methods: Statistics

MeSH: Purinergic P2X Receptor Antagonists*, Receptors, Purinergic P2X3*, Adenosine Triphosphate, Allosteric Regulation, Allosteric Site, Aniline Compounds, Animals, Cryoelectron Microscopy, HEK293 Cells, Humans, Pyridines, Triazines (* major topic)

Journal subjects: Biology and Life Sciences, Cell Biology, Cell Physiology, Receptor Physiology, Research and Analysis Methods, Microscopy, Electron Microscopy, Electron Cryo-Microscopy, Neuroscience, Cognitive Science, Cognitive Psychology, Perception, Sensory Perception, Sensory Receptors, Psychology, Social Sciences, Signal Transduction, Molecular Biology, Molecular Biology Techniques, Mutagenesis and Gene Deletion Techniques, Mutational Analysis, Physiology, Physiological Processes, Coughing, Medicine and Health Sciences, Clinical Medicine, Signs and Symptoms, Biochemistry, Proteins, Transmembrane Receptors, Macromolecular Structure Analysis, Protein Structure, Protein Structure Prediction, Physical Sciences, Chemistry, Computational Chemistry, Molecular Dynamics

Topic: Adenosine and Purinergic Signaling (Physiology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex

Funding: National Natural Science Foundation of China (32471247, 32271244, 32411540020, 82474171); China Postdoctoral Science Foundation (GZC20252599); State Key Laboratory of Genetics and Development of Complex Phenotypes (SKLGDP2502)

Citations: not cited yet (Europe PMC); 70 references in the paper

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

doi:10.17632/crwytdnsdt, at the source; found in “Data Availability”
ebi.ac.uk/pdbe/entry, at EMBL-EBI; found in “Data Availability”

Data Availability

The atomic coordinates of the human P2X3 receptor structures have been deposited in the Protein Data Bank under accession codes 21FG (ATP- and sivopixant-bound, closed) [http://doi.org/10.2210/pdb21FG/pdb] and 21DX (ATP-bound, desensitized) [http://doi.org/10.2210/pdb21DX/pdb], respectively. Cryo-EM maps were deposited in the Electron Microscopy Data Bank (EMDB) under accession codes EMD-67624 (ATP- and sivopixant-bound, closed) [https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-67624] and EMD-67603 (ATP-bound, desensitized) [https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-67603], respectively. All other relevant data are included in the paper or its Supporting information, including S1 Data, or have been deposited in Mendeley Data (https://doi.org/10.17632/crwytdnsdt).

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 11 authors, 12 MeSH terms, 3 funders, 66 references.

Cite

This paper

Zhao, Z., Wang, D.-P., Zhang, X., Gao, Y., Xu, H., Teng, X., Shen, C., Chen, J., Zhang, J., Guo, C.-R., & Hattori, M. (2026). Structure of the human P2X3 receptor reveals the basis for subtype-selective inhibition by sivopixant. PLoS biology, 24(4), e3003777. https://doi.org/10.1371/journal.pbio.3003777

BibTeX

@article{zhao2026structure, author = {Zhao, Zhixuan and Wang, Dong-Ping and Zhang, Xin and Gao, Yuan and Xu, Hexin and Teng, Xinyu and Shen, Cheng and Chen, Jirui and Zhang, Jinru and Guo, Chang-Run and Hattori, Motoyuki}, title = {{Structure of the human P2X3 receptor reveals the basis for subtype-selective inhibition by sivopixant}}, journal = {PLoS biology}, year = {2026}, month = apr, volume = {24}, number = {4}, pages = {e3003777}, publisher = {PLOS}, issn = {1544-9173}, doi = {10.1371/journal.pbio.3003777}, url = {https://doi.org/10.1371/journal.pbio.3003777}, pmid = {42018567}, pmcid = {PMC13132459} }

RIS

TY - JOUR AU - Zhao, Zhixuan AU - Wang, Dong-Ping AU - Zhang, Xin AU - Gao, Yuan AU - Xu, Hexin AU - Teng, Xinyu AU - Shen, Cheng AU - Chen, Jirui AU - Zhang, Jinru AU - Guo, Chang-Run AU - Hattori, Motoyuki TI - Structure of the human P2X3 receptor reveals the basis for subtype-selective inhibition by sivopixant T2 - PLoS biology J2 - PLoS Biol PY - 2026 DA - 2026/04/22 VL - 24 IS - 4 SP - e3003777 SN - 1544-9173 PB - PLOS DO - 10.1371/journal.pbio.3003777 UR - https://doi.org/10.1371/journal.pbio.3003777 LA - en ER -

CSL-JSON

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