9bpc

Publication Abstract from PubMed

ATP-activated P2X3 receptors play a pivotal role in chronic cough, affecting more than 10% of the population. Despite the challenges posed by the highly conserved structure of P2X receptors, efforts to develop selective drugs targeting P2X3 have led to the development of camlipixant, a potent, selective P2X3 antagonist. However, the mechanisms of receptor desensitization, ion permeation, and structural basis of camlipixant binding to P2X3 remain unclear. Here, we report a cryo-EM structure of camlipixant-bound P2X3, revealing a previously undiscovered selective drug-binding site in the receptor. Our findings also demonstrate that conformational changes in the upper body domain, including the turret and camlipixant-binding pocket, play a critical role: turret opening facilitates P2X3 channel closure to a radius of 0.7 A, hindering cation transfer, whereas turret closure leads to channel opening. Structural and functional studies combined with molecular dynamics simulations provide a comprehensive understanding of camlipixant's selective inhibition of P2X3, offering a foundation for future drug development targeting this receptor.

Mechanistic insights into the selective targeting of P2X3 receptor by camlipixant antagonist.,Thach T, Dhanabalan K, Nandekar PP, Stauffer S, Heisler I, Alvarado S, Snyder J, Subramanian R J Biol Chem. 2025 Jan;301(1):108109. doi: 10.1016/j.jbc.2024.108109. Epub 2024 , Dec 18. PMID:39706278^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.