RT Journal Article
SR Electronic
T1 A Second Drug Binding Site in P2X3
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2024.06.10.598171
DO 10.1101/2024.06.10.598171
A1 Thach, Trung
A1 Dhanabalan, KanagaVijayan
A1 Nandekar, Prajwal Prabhakarrao
A1 Stauffer, Seth
A1 Heisler, Iring
A1 Alvarado, Sarah
A1 Snyder, Jonathan
A1 Subramanian, Ramaswamy
YR 2024
UL http://biorxiv.org/content/early/2024/06/14/2024.06.10.598171.abstract
AB Purinergic P2X3 receptors form trimeric cation-gated channels, which are activated by extracellular ATP. P2X3 plays a crucial role in chronic cough and affects over 10% of the population. Despite considerable efforts to develop drugs targeting P2X3, the highly conserved structure within the P2X receptor family presents obstacles for achieving selectivity. Camlipixant, a potent and selective P2X3 antagonist, is currently in phase III clinical trials. However, the mechanisms underlying receptor desensitization, ion permeation, principles governing antagonism, and the structure of P2X3 when bound to camlipixant remain elusive. In this study, we established a stable cell line expressing homotrimeric P2X3 and utilized a peptide scaffold to purify the complex and determine its structure using cryo-electron microscopy (cryo-EM). P2X3 binds to camlipixant at a previously unidentified drug-binding site and functions as an allosteric inhibitor. Structure-activity studies combined with modeling and simulations have shed light on the mechanisms underlying the selective targeting and inhibition of P2X3 by camlipixant, distinguishing it from other members of the P2X receptor family.Competing Interest StatementThe Research was funded by Elanco Animal Health and some of the authors work for Elanco Animal Health.