Fig. 10: Mechanism of species-specific differences in P2X7 receptor inhibitors between humans and rodents, and the construction of mice to eliminate these differences.
From: Understanding interspecies drug response variations between human and rodent P2X7 receptors
Inhibitors binding to the P2X7 receptor exhibit varying depths of entry into the portal of the central pocket (PCP), leading to occupancy of different sub-pockets (PCP1-3). The deepest sub-pocket, PCP1, surrounded by rigid β-sheets (β4, β7, and β8), has a high probability of producing species-specific differences in its bound inhibitors, with the amino acid at position 312 of β8 in PCP1, the narrowest middle of PCP, being a key factor. P2rx7A312V/A312V mice can eliminate these species-specific differences between humans and rodents, facilitating the development of relevant mouse disease models and advancing these inhibitors toward clinical trials. hP2X7 human P2X7, mP2X7 mouse P2X7.
