Guanylate-binding proteins (GBPs) are interferon-inducible guanosine triphosphate hydrolases (GTPases) mediating host defense against intracellular pathogens. Their antimicrobial activity hinges on their ability to self-associate and coat pathogen-associated compartments or cytosolic bacteria. Coat formation depends on GTPase activity but how nucleotide binding and hydrolysis prime coat formation remains unclear. Here, we report the cryo-electron microscopy structure of the full-length human GBP1 dimer in its guanine nucleotide-bound state and describe the molecular ultrastructure of the GBP1 coat on liposomes and bacterial lipopolysaccharide membranes. Conformational changes of the middle and GTPase effector domains expose the isoprenylated C terminus for membrane association. The α-helical middle domains form a parallel, crossover arrangement essential for coat formation and position the extended effector domain for intercalation into the lipopolysaccharide layer of gram-negative membranes. Nucleotide binding and hydrolysis create oligomeric scaffolds with contractile abilities that promote membrane extrusion and fragmentation. Our data offer a structural and mechanistic framework for understanding GBP1 effector functions in intracellular immunity.

鸟苷酸结合蛋白 （GBPs） 是干扰素诱导的鸟苷三磷酸水解酶 （GTP ases），介导宿主对细胞内病原体的防御。它们的抗菌活性取决于它们自缔合和包被病原体相关隔室或胞质细菌的能力。包被的形成取决于 GTP 酶活性，但核苷酸结合和水解引物包被的形成方式仍不清楚。在这里，我们报道了处于鸟嘌呤核苷酸结合状态的全长人 GBP1 二聚体的冷冻电子显微镜结构，并描述了脂质体和细菌脂多糖膜上 GBP1 涂层的分子超微结构。中间和 GTP 酶效应结构域的构象变化暴露了异戊二烯化的 C 末端用于膜结合。α 螺旋中间结构域形成平行的交叉排列，对外壳形成至关重要，并将扩展的效应结构域定位为嵌入革兰氏阴性膜的脂多糖层。核苷酸结合和水解产生具有收缩能力的寡聚支架，促进膜挤出和碎裂。我们的数据为理解细胞内免疫中的 GBP1 效应器功能提供了一个结构和机制框架。