The human integral membrane protein SERINC5 potently restricts HIV-1 infectivity and sensitizes the virus to antibody-mediated neutralization. Here, using cryo-EM, we determine the structures of human SERINC5 and its orthologue from Drosophila melanogaster at subnanometer and near-atomic resolution, respectively. The structures reveal a novel fold comprised of ten transmembrane helices organized into two subdomains and bisected by a long diagonal helix. A lipid binding groove and clusters of conserved residues highlight potential functional sites. A structure-based mutagenesis scan identified surface-exposed regions and the interface between the subdomains of SERINC5 as critical for HIV-1-restriction activity. The same regions are also important for viral sensitization to neutralizing antibodies, directly linking the antiviral activity of SERINC5 with remodeling of the HIV-1 envelope glycoprotein.

人类整合膜蛋白 SERINC5 有效限制 HIV-1 的感染性并使病毒对抗体介导的中和作用敏感。在这里，我们使用冷冻电镜，分别以亚纳米和近原子分辨率确定了人类 SERINC5 及其来自果蝇的直系同源物的结构。这些结构揭示了一种新颖的折叠，由十个跨膜螺旋组成，这些螺旋组织成两个子域，并被长对角螺旋一分为二。脂质结合沟和保守残基簇突出了潜在的功能位点。基于结构的诱变扫描发现表面暴露区域和 SERINC5 子结构域之间的界面对于 HIV-1 限制活性至关重要。这些区域对于病毒对中和抗体的敏感性也很重要，将 SERINC5 的抗病毒活性与 HIV-1 包膜糖蛋白的重塑直接联系起来。