Structural mechanism of SGLT1 inhibitors

Yange Niu, Wenhao Cui, Rui Liu, Sanshan Wang, Han Ke, Xiaoguang Lei and Lei Chen ()
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Yange Niu: Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
Wenhao Cui: Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
Rui Liu: Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
Sanshan Wang: Peking University
Han Ke: Peking University
Xiaoguang Lei: Peking University
Lei Chen: Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-33421-7

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