{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Guo CR"],"funding":["National Natural Science Foundation of China (National Science Foundation of China)"],"pagination":["10827"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12673082"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["16(1)"],"pubmed_abstract":["Despite intensive development, P2X7 modulators have struggled in translation due to human genetic variability and species-dependent drug responses. Here, we identify PSFL1191, a portal-of-central-pocket (PCP)-site inhibitor selective for human and panda P2X7, but inactive against rodents. Cryo-EM structures revealed two distinct PCP sub-pockets: PCP1, a rigid base pocket demanding precise steric complementarity with PSFL1191, and PCP2, a conserved middle cavity targeted by JNJ-54175446, a clinical candidate unaffected by species differences. Species selectivity maps to a deep PCP1 motif (V312-Y295-M105-F103-P96). In P2rx7<sup>A312V/A312V</sup> mice, PSFL1191 markedly altered macrophage-mediated bacterial clearance and wound healing while preserving basal physiology, effects absent in wild-"],"journal":["Nature communications"],"pubmed_title":["Understanding interspecies drug response variations between human and rodent P2X7 receptors."],"pmcid":["PMC12673082"],"funding_grant_id":["32371289"],"pubmed_authors":["Liu H","Li J","Guo CR","Chen J","Wang DP","Shen C","Zhou Y","Sheng D","Li JY","Zhang R","Wang J","Jin F","Huang Y","Zhao YY","Yao JB","Li TT","Cao P","Hattori M","Yu Y"],"additional_accession":[]},"is_claimable":false,"name":"Understanding interspecies drug response variations between human and rodent P2X7 receptors.","description":"Despite intensive development, P2X7 modulators have struggled in translation due to human genetic variability and species-dependent drug responses. Here, we identify PSFL1191, a portal-of-central-pocket (PCP)-site inhibitor selective for human and panda P2X7, but inactive against rodents. Cryo-EM structures revealed two distinct PCP sub-pockets: PCP1, a rigid base pocket demanding precise steric complementarity with PSFL1191, and PCP2, a conserved middle cavity targeted by JNJ-54175446, a clinical candidate unaffected by species differences. Species selectivity maps to a deep PCP1 motif (V312-Y295-M105-F103-P96). In P2rx7<sup>A312V/A312V</sup> mice, PSFL1191 markedly altered macrophage-mediated bacterial clearance and wound healing while preserving basal physiology, effects absent in wild-","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Dec","modification":"2026-06-11T04:44:58.143Z","creation":"2026-06-11T03:07:52.431Z"},"accession":"S-EPMC12673082","cross_references":{"pubmed":["41330895"],"doi":["10.1038/s41467-025-65847-0"]}}