钠-葡萄糖协同转运蛋白1抑制剂的结构机制。
Structural mechanism of SGLT1 inhibitors.
作者信息
Niu Yange, Cui Wenhao, Liu Rui, Wang Sanshan, Ke Han, Lei Xiaoguang, Chen Lei
机构信息
State Key Laboratory of Membrane Biology, College of Future Technology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Beijing, China.
National Biomedical Imaging Center, Peking University, Beijing, China.
出版信息
Nat Commun. 2022 Oct 28;13(1):6440. doi: 10.1038/s41467-022-33421-7.
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.
钠葡萄糖共转运蛋白（SGLT）利用钠的电化学梯度驱动葡萄糖逆浓度梯度穿过质膜进行转运。人类SGLT1（hSGLT1）在从食物中摄取糖分过程中起关键作用，其抑制剂在多种疾病治疗中显示出前景。然而，hSGLT1的抑制机制仍不清楚。在此，我们展示了在高亲和力抑制剂LX2761存在下hSGLT1-MAP17异二聚体复合物的冷冻电镜结构。LX2761通过楔入hSGLT1的底物结合位点和细胞外前庭，将转运蛋白锁定在向外开放的构象。LX2761阻断了hSGLT1假定的水渗透途径。该结构还揭示了hSGLT1从向外开放状态转变为向内开放状态期间的构象变化。
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