An essential protein of the SARS-CoV-2 virus, the envelope protein E, forms a homopentameric cation channel that is important for virus pathogenicity. Here we report a 2.1-Å structure and the drug-binding site of E’s transmembrane domain (ETM), determined using solid-state NMR spectroscopy. In lipid bilayers that mimic the endoplasmic reticulum–Golgi intermediate compartment (ERGIC) membrane, ETM forms a five-helix bundle surrounding a narrow pore. The protein deviates from the ideal α-helical geometry due to three phenylalanine residues, which stack within each helix and between helices. Together with valine and leucine interdigitation, these cause a dehydrated pore compared with the viroporins of influenza viruses and HIV. Hexamethylene amiloride binds the polar amino-terminal lumen, whereas acidic pH affects the carboxy-terminal conformation. Thus, the N- and C-terminal halves of this bipartite channel may interact with other viral and host proteins semi-independently. The structure sets the stage for designing E inhibitors as antiviral drugs.

SARS-CoV-2 病毒的一种必需蛋白，包膜蛋白 E，形成对病毒致病性很重要的同源五聚体阳离子通道。在这里，我们报告了 E 跨膜结构域 (ETM) 的 2.1-Å 结构和药物结合位点，这是使用固态 NMR 光谱确定的。在模拟内质网-高尔基中间室 (ERGIC) 膜的脂质双层中，ETM 形成围绕狭窄孔的五螺旋束。由于每个螺旋内和螺旋之间堆叠了三个苯丙氨酸残基，该蛋白质偏离了理想的 α 螺旋几何形状。与流感病毒和 HIV 的病毒孔蛋白相比，这些与缬氨酸和亮氨酸相互交叉会导致孔脱水。六亚甲基阿米洛利结合极性氨基末端管腔，而酸性 pH 则影响羧基末端构象。因此，该二分通道的 N 端和 C 端半部可能与其他病毒和宿主蛋白半独立地相互作用。该结构为将 E 抑制剂设计为抗病毒药物奠定了基础。