Structural mechanism of SGLT1 inhibitors

Yange Niu; Wenhao Cui; Rui Liu; Sanshan Wang; Han Ke; Xiaoguang Lei; Lei Chen

doi:10.1038/s41467-022-33421-7

Structural mechanism of SGLT1 inhibitors

Nat Commun. 2022 Oct 28;13(1):6440. doi: 10.1038/s41467-022-33421-7.

Authors

Yange Niu^#^{1

2}, Wenhao Cui^#^{1

2

3}, Rui Liu^{1

2}, Sanshan Wang^{4

5}, Han Ke^{4

5}, Xiaoguang Lei^{4

5}, Lei Chen^{6

7

8}

Affiliations

¹ 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.
² National Biomedical Imaging Center, Peking University, Beijing, China.
³ Taishan College, Shandong University, Qingdao, China.
⁴ Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
⁵ Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, Beijing, China.
⁶ 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. chenlei2016@pku.edu.cn.
⁷ National Biomedical Imaging Center, Peking University, Beijing, China. chenlei2016@pku.edu.cn.
⁸ Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China. chenlei2016@pku.edu.cn.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Benzhydryl Compounds*
Glucose / metabolism
Humans
Sodium / metabolism
Thioglycosides*

Substances

Benzhydryl Compounds
Glucose
LX2761
Sodium
Thioglycosides
SLC5A1 protein, human