biostudies-literatureGuo CRNational Natural Science Foundation of China (National Science Foundation of China)10827https://www.ebi.ac.uk/biostudies/studies/S-EPMC12673082biostudies-literatureUnknown16(1)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^A312V/A312V mice, PSFL1191 markedly altered macrophage-mediated bacterial clearance and wound healing while preserving basal physiology, effects absent in wild-Nature communicationsUnderstanding interspecies drug response variations between human and rodent P2X7 receptors.PMC1267308232371289Liu HLi JGuo CRChen JWang DPShen CZhou YSheng DLi JYZhang RWang JJin FHuang YZhao YYYao JBLi TTCao PHattori MYu YfalseUnderstanding interspecies drug response variations between human and rodent P2X7 receptors.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^A312V/A312V mice, PSFL1191 markedly altered macrophage-mediated bacterial clearance and wound healing while preserving basal physiology, effects absent in wild-2025-01-01T00:00:00Z2025 Dec2026-06-11T04:44:58.143Z2026-06-11T03:07:52.431ZS-EPMC126730824133089510.1038/s41467-025-65847-0