Kimball Ian H, Nguyen Phuong T, Olivera Baldomero M, Sack Jon T, Yarov-Yarovoy Vladimir
Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA, United States.
Department of Biology, University of Utah, Salt Lake City, UT, United States.
Front Pharmacol. 2023 Mar 16;14:1156855. doi: 10.3389/fphar.2023.1156855. eCollection 2023.
The voltage-gated sodium (Na) channel subtype Na1.7 plays a critical role in pain signaling, making it an important drug target. Here we studied the molecular interactions between μ-Conotoxin KIIIA (KIIIA) and the human Na1.7 channel (hNa1.7). We developed a structural model of hNa1.7 using Rosetta computational modeling and performed docking of KIIIA using RosettaDock to predict residues forming specific pairwise contacts between KIIIA and hNa1.7. We experimentally validated these contacts using mutant cycle analysis. Comparison between our KIIIA-hNa1.7 model and the cryo-EM structure of KIIIA-hNa1.2 revealed key similarities and differences between Na channel subtypes with potential implications for the molecular mechanism of toxin block. The accuracy of our integrative approach, combining structural data with computational modeling, experimental validation, and molecular dynamics simulations, suggests that Rosetta structural predictions will be useful for rational design of novel biologics targeting specific Na channels.
电压门控钠（Na）通道亚型Na1.7在疼痛信号传导中起关键作用，使其成为重要的药物靶点。在此，我们研究了μ-芋螺毒素KIIIA（KIIIA）与人类Na1.7通道（hNa1.7）之间的分子相互作用。我们使用Rosetta计算建模开发了hNa1.7的结构模型，并使用RosettaDock对KIIIA进行对接，以预测形成KIIIA与hNa1.7之间特定成对接触的残基。我们使用突变循环分析对这些接触进行了实验验证。我们的KIIIA-hNa1.7模型与KIIIA-hNa1.2的冷冻电镜结构之间的比较揭示了钠通道亚型之间的关键异同，这可能对毒素阻断的分子机制具有影响。我们将结构数据与计算建模、实验验证和分子动力学模拟相结合的综合方法的准确性表明，Rosetta结构预测将有助于针对特定钠通道的新型生物制剂的合理设计。
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