| 1 | Molecular mechanism underlying the subtype-selectivity of competitive inhibitor NF110 and its distinct potencies in human and rat P2X3 receptors显示文摘P2X receptors are a family of extracellular ATP-gated trimeric cation channels that is widely distributed in human tissues. Quite some drug candidates targeting P2X receptors have entered into preclinical or main phases of clinical trials, but many of them failed due to low subtype-selectivity or species differences in pharmacological activities between human and experimental animals. Here, we identified the distinct inhibitory efficacies of NF110, a competitive inhibitor, between the rat(rP2X3) and human(hP2X3) P2X3 receptors. We demonstrated that this difference is determined by two amino acids located in the dorsal fin(DF) domain of P2X3 receptors. As revealed by mutagenesis, metadynamics, and covalent modification, NF110-mediated rP2X3 inhibition may be through a filling in the cavity formed by the DF,left flipper(LF) and lower body(LB) to partially, rather than fully, occupy the ATP-binding pocket.Moreover, substitution of residues located in the DF and/or LF domains of the rP2X2 receptor, a NF110-insensitive subtype, with the equivalent amino acids of rP2X3, bestowed the sensitivity of rP2X2 to NF110. The critical roles of the DF and LF domains in channel gating of P2X and low conservativity in residue sequences of those two domains raise the possibility that small molecules differentially interacting with the residues of the DF and LF domains of different P2X receptors may modulate channel's activity in a subtype-selective manner. However, the possible species-specificity of P2X inhibitors/modulators makes it more complex when interpreting the preclinical data into clinical researches.Nevertheless, our data provide new insights into the subtype-selectivity of competitive inhibitors and their distinct potencies in the human and experimental animals, both of which are extremely important in the drug discovery of P2X receptors. | Bin Li Jin Wang Xiaoyang Cheng Yan Liu Yang Yang Xiaona Yang Changrun Guod Youya Niu Peng Cao Xiangyang Lu Michael X.Zhu Yun Tian Ye Yu | 2018 | Science Bulletin2018，63，24： | 1 |
| 2 | X-site doping in ABX_(3) triggers phase transition and higher T_(c) of the dielectric switch in perovskite显示文摘Material stability is always the key factor for applied materials especially the working environment that requires higher temperature sensitivity or temperature fluctuation range.In which,the stimulus-response perovskite materials are just sensitive to stability to ensure the accuracy and stability of the signals,in the applied devices of batteries and memory storage devices and so on.However,it is still a tremendous challenge to improve the stability of perovskite materials,and maintain reliability in the devices.Here,a novel ABX_(2)X'_(1)(X-site doping in an ABX_(3))compound[CEMP]-[CdBr_(2)(SCN)](1,CEMP=1-(2-chloro-ethyl)-1-methyl-piperidine)with remarkable high-temperature reversible dielectric switching behavior was proposed.The strategy of[SCN]^(−)doping in perovskite for improving the stability was successfully achieved.Meanwhile,the steric hindrance is increased while the energy barrier is also increased by replacing hydrogen with flexible groups,which leads to a high-temperature reversible phase transition.The new finding provides a new direction to enrich new applications and design ideas of perovskite materials.Especially the X-site strategy of doping or substitution in the ABX_(3),it will promote ingenious and perfect experimental results in material synthesis and performance improvement by chemistry disciplines. | Youya Yu Peizhi Huang Yuzhen Wang Zhixu Zhang Tie Zhang Yi Zhang Dawei Fu | 2021 | Chinese Chemical Letters2021，32，11： | 1 |
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