Structural Basis of PANX1 Permeation and Positive Modulation by Mefloquine

Authors

Yangyang Li
Zheng Ruan, Thomas Jefferson UniversityFollow
Junuk Lee
Ian Orozco
Edward Zhou
Juan Du
Wei Lü

Document Type

Article

Publication Date

12-11-2025

Comments

This article is the author’s final published version in BMJ Open, Volume 16, issue 1, 2025, Article number 11057.

The published version is available at https://doi.org/10.1038/s41467-025-66028-9. Copyright © The Author(s) 2025.

Abstract

Purinergic signaling relies on ATP release through exocytosis and large-pore channels. Large-pore channels permeate both small anions like chloride and large signaling molecules like ATP, but how this broad cargo selectivity is structurally controlled remains elusive. Here we investigate PANX1, a prototypical large-pore channel, and uncover structural plasticity at the extracellular entrance formed by seven tryptophan (W74) residues. The W74 sidechains are flexible, sampling conformations that range from a constricted state permissive only to chloride to a dilated state compatible with ATP. These states are coupled to variable cation-π interactions between W74 and arginine 75 (R75), suggesting a mechanism for dynamic tuning of pore architecture and selective cargo permeation. We also identify mefloquine as a positive modulator of PANX1 that binds near the side tunnel to control ion flow through this pathway. Together, these findings define the structural principles underlying PANX1 permeation and modulation.

Recommended Citation

Li, Yangyang; Ruan, Zheng; Lee, Junuk; Orozco, Ian; Zhou, Edward; Du, Juan; and Lü, Wei, "Structural Basis of PANX1 Permeation and Positive Modulation by Mefloquine" (2025). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 293.
https://jdc.jefferson.edu/bmpfp/293

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

PubMed ID

41381453

Language

English