Voltage-gated sodium (Na_v) and calcium (Ca_v) channels are responsible for the initiation of electrical signals. They have long been targeted for the treatment of various diseases. The mounting number of cryoelectron microscopy (cryo-EM) structures for diverse subtypes of Na_v and Ca_v channels from multiple organisms necessitates a generic residue numbering system to establish the structure-function relationship and to aid rational drug design or optimization. Here we suggest a structure-based residue numbering scheme, centering around the most conserved residues on each of the functional segments. We elaborate the generic numbers through illustrative examples, focusing on representative drug-binding sites of eukaryotic Na_v and Ca_v channels. We also extend the numbering scheme to compare common disease mutations among different Na_v subtypes. Application of the generic residue numbering scheme affords immediate insights into hotspots for pathogenic mutations and critical loci for drug binding and will facilitate drug discovery targeting Na_v and Ca_v channels.

电压门控钠 (Na _v ) 和钙 (Ca _v ) 通道负责电信号的启动。长期以来，它们一直是治疗各种疾病的目标。来自多种生物体的 Na _v和 Ca _v通道的不同亚型的冷冻电镜 (cryo-EM) 结构的数量不断增加，需要通用的残基编号系统来建立结构-功能关系并帮助合理的药物设计或优化。在这里，我们建议一种基于结构的残基编号方案，以每个功能片段上最保守的残基为中心。我们通过说明性示例详细阐述了通用数字，重点关注真核 Na _v和 Ca _v通道的代表性药物结合位点。我们还扩展了编号方案来比较不同 Na _v亚型之间的常见疾病突变。通用残基编号方案的应用可以立即洞察致病突变的热点和药物结合的关键位点，并将促进针对 Na _v和 Ca _v通道的药物发现。