Sodium glucose co-transporters (SGLT) harness the electrochemical gradient of sodium to drive the uphill transport of glucose across the plasma membrane. Human SGLT1 (hSGLT1) plays a key role in sugar uptake from food and its inhibitors show promise in the treatment of several diseases. However, the inhibition mechanism for hSGLT1 remains elusive. Here, we present the cryo-EM structure of the hSGLT1-MAP17 hetero-dimeric complex in the presence of the high-affinity inhibitor LX2761. LX2761 locks the transporter in an outward-open conformation by wedging inside the substrate-binding site and the extracellular vestibule of hSGLT1. LX2761 blocks the putative water permeation pathway of hSGLT1. The structure also uncovers the conformational changes of hSGLT1 during transitions from outward-open to inward-open states.

钠葡萄糖协同转运蛋白 (SGLT) 利用钠的电化学梯度来驱动葡萄糖向上运输穿过质膜。人类 SGLT1 (hSGLT1) 在从食物中摄取糖分方面起着关键作用，其抑制剂在多种疾病的治疗中显示出前景。然而，hSGLT1 的抑制机制仍然难以捉摸。在这里，我们展示了在高亲和力抑制剂 LX2761 存在的情况下 hSGLT1-MAP17 异二聚体复合物的冷冻电镜结构。LX2761 通过嵌入 hSGLT1 的底物结合位点和细胞外前庭内部，将转运蛋白锁定在向外开放的构象中。LX2761 阻断 hSGLT1 的假定水渗透途径。该结构还揭示了 hSGLT1 在从向外开放状态转变为向内开放状态期间的构象变化。