颜宁团队发表最新PNAS论文：助力心脏病及抗癫痫/镇痛药物精准设计

Core Viewpoint - The research highlights the structural differences between TTX-resistant (TTXr) and TTX-sensitive (TTXs) sodium channels, providing insights for the development of subtype-selective sodium channel-targeted drugs [4][5]. Group 1: Research Findings - The study published in PNAS by researchers from Shenzhen Medical Academy and Tsinghua University reveals that the differences in affinity for tetrodotoxin (TTX) and the β1 subunit between TTXr and TTXs sodium channels stem from several key structural elements [4][5]. - The research reported a 3.4 Å resolution structure of the wild-type human Na v 1.5 channel co-expressed with the β1 subunit after treatment with high concentrations of TTX, elucidating the molecular mechanisms behind the response differences to TTX and the β subunit [5][6]. - The study identified four critical sites on the extracellular loop (ECL) that may determine the differences in β1 subunit binding capabilities between Na v 1.5 and other sodium channels [6][7]. Group 2: Structural Insights - In TTXs sodium channels, the guanidinium group of TTX interacts with conserved cation-π interactions, which are lost in TTXr channels due to substitutions at corresponding sites, explaining the sensitivity differences [6][7]. - The absence of key cysteine residues in the ECL II domain of TTXr channels, which are necessary for forming disulfide bonds with β2 or β4 subunits, emphasizes the critical role of the extracellular loop in the mechanistic differences between TTXs and TTXr sodium channels [7].