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TitleMechanistic insights into the selective targeting of P2X3 receptor by camlipixant antagonist.
Journal, issue, pagesJ Biol Chem, Vol. 301, Issue 1, Page 108109, Year 2025
Publish dateDec 18, 2024
AuthorsTrung Thach / KanagaVijayan Dhanabalan / Prajwal Prabhakarrao Nandekar / Seth Stauffer / Iring Heisler / Sarah Alvarado / Jonathan Snyder / Ramaswamy Subramanian /
PubMed AbstractATP-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 ...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 Å, 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.
External linksJ Biol Chem / PubMed:39706278 / PubMed Central
MethodsEM (single particle)
Resolution3.44 - 3.63 Å
Structure data

44771

9bpc

EMDB-44771, PDB-9bpc:
Cryo-EM structure of P2X3 receptor in complex with camlipixant
Method: EM (single particle) / Resolution: 3.44 Å

44772

9bpd

EMDB-44772, PDB-9bpd:
Cryo-EM structure of P2X3 receptor in complex with ATP:Mg2+
Method: EM (single particle) / Resolution: 3.63 Å

Chemicals

PDB-1aqx:
GLUTATHIONE S-TRANSFERASE IN COMPLEX WITH MEISENHEIMER COMPLEX

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

ChemComp-MG:
Unknown entry

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

Source
  • canis lupus (wolf)
KeywordsMEMBRANE PROTEIN / P2X3 / camlipixant / cryo-EM / ion channel / receptor

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