The P-type ATPase ATP7B exports cytosolic copper and plays an essential role in the regulation of cellular copper homeostasis. Mutants of ATP7B cause Wilson disease (WD), an autosomal recessive disorder of copper metabolism. Here, we present cryoelectron microscopy (cryo-EM) structures of human ATP7B in the E1 state in the apo, the putative copper-bound, and the putative cisplatin-bound forms. In ATP7B, the N-terminal sixth metal-binding domain (MBD6) binds at the cytosolic copper entry site of the transmembrane domain (TMD), facilitating the delivery of copper from the MBD6 to the TMD. The sulfur-containing residues in the TMD of ATP7B mark the copper transport pathway. By comparing structures of the E1 state human ATP7B and E2-P_i state frog ATP7B, we propose the ATP-driving copper transport model of ATP7B. These structures not only advance our understanding of the mechanisms of ATP7B-mediated copper export but can also guide the development of therapeutics for the treatment of WD.

P 型 ATP 酶 ATP7B 输出胞质铜，在调节细胞铜稳态中起着重要作用。ATP7B的突变体会导致威尔逊病 (WD)，这是一种铜代谢的常染色体隐性遗传病。在这里，我们展示了载脂蛋白 E1 状态下人类 ATP7B 的低温电子显微镜 (cryo-EM) 结构、假定的铜结合形式和假定的顺铂结合形式。在 ATP7B 中，N 末端第六金属结合结构域 (MBD6) 结合跨膜结构域 (TMD) 的胞质铜进入位点，促进铜从 MBD6 到 TMD 的输送。ATP7B TMD 中的含硫残基标志着铜转运途径。通过比较 E1 状态人类 ATP7B 和 E2-P _i的结构state frog ATP7B，我们提出了 ATP7B 的 ATP 驱动铜传输模型。这些结构不仅促进了我们对 ATP7B 介导的铜输出机制的理解，而且还可以指导 WD 治疗药物的开发。