Discovery of an allosteric binding site for anthraquinones at the human P2X4 receptor.

ABSTRACT: P2X receptors are trimeric ATP-gated ion channels. The P2X4 receptor subtype is a promising drug target for the treatment of inflammatory diseases, neuropathic pain, and cancer. Here, the water-soluble anthraquinone derivative Cibacron Blue, previously described as a P2X4 receptor modulator, is selected as a lead structure, and structure-activity relationships are investigated. A chimeric receptor approach, combined with mutagenesis and docking studies, is applied to identify the allosteric binding site and the interacting amino acid residues. We discover that Glu307, located in the upper body of the receptor, is prone to form an intermolecular "ionic lock" with basic amino acid residues, thereby preventing high-affinity binding of anthraquinone derivatives. Exchange of Glu307 for threonin

SUBMITTER: Nagel J 

PROVIDER: S-EPMC12678798 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature