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Structural basis of inhibition of the human SGLT2–MAP17 glucose transporter


Human sodium–glucose cotransporter 2 (hSGLT2) mediates the reabsorption of the majority of filtrated glucose in the kidney1. Pharmacological inhibition of hSGLT2 by oral small-molecule inhibitors, such as empagliflozin, leads to enhanced excretion of glucose and is widely used in the clinic to manage blood glucose levels for the treatment of type 2 diabetes1. Here we determined the cryogenic electron microscopy structure of the hSGLT2–MAP17 complex in the empagliflozin-bound state to an overall resolution of 2.95 Å. Our structure shows eukaryotic SGLT-specific structural features. MAP17 interacts with transmembrane helix 13 of hSGLT2. Empagliflozin occupies both the sugar-substrate-binding site and the external vestibule to lock hSGLT2 in an outward-open conformation, thus inhibiting the transport cycle. Our work provides a framework for understanding the mechanism of SLC5A family glucose transporters and also develops a foundation for the future rational design and optimization of new inhibitors targeting these transporters.

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Fig. 1: Architecture of the hSGLT2–MAP17 complex.
Fig. 2: The eukaryotic-specific features of hSGLT2.
Fig. 3: The empagliflozin-binding site of hSGLT2.
Fig. 4: Empagliflozin locks hSGLT2 in the outward-facing conformation.

Data availability

Cryo-EM maps and atomic coordinates of the hSGLT2–MAP17 complex have been deposited in the Electron Microscopy Data Bank and PDB under the ID codes EMD-31558 and 7FEN, respectively. Source data are provided with this paper.


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We thank J. Ye and W. Zhang from Boehringer Ingelheim International GmbH for assistance; L.-C. Hsu from the School of Pharmacy, National Taiwan University for providing the 1-NBD-glucose sample for our initial pilot experiment; and S. Huang for assistance with the radioactive experiments. Cryo-EM data collection was supported by the Electron Microscopy Laboratory and Cryo-EM Platform of Peking University with the assistance of X. Li, Z. Guo, B. Shao, X. Pei and G. Wang. Part of the structural computation was also performed on the Computing Platform of the Center for Life Science and High-performance Computing Platform of Peking University. We thank the National Center for Protein Sciences at Peking University in Beijing, China, for assistance with negative-stain EM. The work is supported by grants from the National Natural Science Foundation of China (91957201 and 31870833 to L.C., 31821091 to L.C. and Z.C., and 31971375 to Z.C.) and Beijing Municipal Science & Technology Commission Project (Z201100005320017 to Z.C.). C.G. was partially supported by a postdoctoral fellowship sponsored by Boehringer Ingelheim International GmbH.

Author information

Authors and Affiliations



L.C. initiated the project and wrote the draft of the manuscript. C.G. screened the SGLT homologues. Y.N. purified protein, prepared the cryo-EM sample, processed data and carried out functional assays. Y.N. and R.L. collected the cryo-EM data. L.C. built and refined the model. Y.Z. and Z.C. synthesized 1-NBD-glucose. S.H. and H.N. provided empagliflozin and [3H]-empagliflozin. All authors contributed to the preparation of the manuscript.

Corresponding author

Correspondence to Lei Chen.

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Competing interests

S.H. and H.N. are employees of Boehringer Ingelheim Pharma, GmbH & Co KG.

Additional information

Peer review information Nature thanks David Drew and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data figures and tables

Extended Data Fig. 1 Biochemical characterization of the human SGLT2-MAP17 heterodimer.

a, FSEC traces of GFP-tagged hSGLT2 (red) alone, in complex with non-tagged MAP17 (green) and in complex with C-terminal MBP-mScarlet tagged MAP17 (blue). The fluorescence signals were monitored in the GFP channel. b, HPLC chromatograph of synthesized 1-NBD-glucose, showing high purity. ESI-MS: m/z calculated for C12H14N4O8 [M+H]+ 343.09, found 343.18. c, [3H]-empagliflozin binding to the purified hSGLT2-MAP17 protein. Unlabeled empagliflozin was used for competition. CPM, counts per minute. (Data are shown as means ± standard deviations, n = 3 biologically independent samples). d, Size-exclusion chromatography profile of the hSGLT2-MAP17 complex in nanodisc in the presence of empagliflozin. Fractions between dashes were used for cryo-EM sample preparation. e, SDS-PAGE gel of purified hSGLT2-MAP17 protein in the nanodisc. Asterisk indicates the fraction for cryo-EM sample preparation. The purifications were repeated 3 times with similar results. (For gel source data, see Supplementary Fig. 1.).

Source data

Extended Data Fig. 2 Cryo-EM image analysis of the hSGLT2-MAP17 complex.

a, Representative raw micrograph of hSGLT2-MAP17 complex in nanodisc. The other 7899 micrographs are similar to this one. b, 2D class averages of hSGLT2-MAP17 complex output from cryoSPARC. c, Data processing flow chart. d, The locations of GFP (green) and nanobody (brown) shown in 4 Å low-pass filtered cryo-EM map. e, Gold-standard Fourier shell correlation curves of the final reconstruction. f, Angular distributions of the final reconstruction. g, Local resolution distribution of the hSGLT2-MAP17 complex. h, The cut-open view of local resolution distribution of the hSGLT2-MAP17 complex.

Source data

Extended Data Fig. 3 Representative cryo-EM density maps of the hSGLT2-MAP17 complex.

The densities of transmembrane helices, empagliflozin, and putative palmitoylated Cys residues are contoured at 1.3 σ, 1.0 σ and 1.0 σ, respectively.

Extended Data Fig. 4 Sequence alignment of SGLT.

a, The sequences of the Homo sapiens SGLT2 (hSGLT2), Mus Musculus SGLT2 (mSGLT2), Homo sapiens SGLT1 (hSGLT1), and Vibrio parahaemolyticus SGLT (vSGLT) are aligned using MEGA-X. α helices are shown as cylinders. Unmodeled residues are shown as dashed lines. Conserved residues are colored from cyan to blue. Residues that form disulfide bonds are highlighted in yellow. FRG mutations on extracellular protrusion are indicated by asterisks. The residues that are mutated in Fig. 3g are boxed in red. The colors of cylinders are the same as in Fig. 1d. b, The sequences of transmembrane helices of Homo sapiens MAP17, Homo sapiens SMIM24 are aligned using MEGA-X. Conserved residues are colored from cyan to blue. Residues that interact with hSGLT2 are boxed in red. c, The superposition of hSGLT2 (colored) with vSGLT (gray). The scaffold domain of hSGLT2 is colored in green. The bundle helices of TM1, TM2, TM6 and TM7 of hSGLT2 are colored in brown, blue, pink and red respectively. d, A 90° rotated view of c. e, Interactions between hydroxyl groups of empagliflozin and hSGLT2. The helices of hSGLT2 are colored the same as in c. Empagliflozin and its interacting residues are shown as sticks. Putative hydrogen bonds are depicted as black dashed lines. f, Interactions of D-galactose with vSGLT. The helices of vSGLT are numbered according to LeuT nomenclature for comparison. D-galactose and its interacting residues are shown as sticks. Hydrogen bonds are depicted as black dashed lines. g, Top view of the cross-section of the transmembrane domain of the hSGLT2-MAP17 complex at the approximate level indicated by the dashed lines in Fig. 1c, colored the same as in Fig. 1c. The numbers of transmembrane helices are labeled above. h, Top view of the cross-section of the transmembrane domain of the GkApcT-MgtS complex. GkApcT is colored in grey and MgtS is colored in yellow. i, Top view of the cross-section of the transmembrane domain of the LAT1-4F2hc complex. LAT1 is colored in grey and the transmembrane helix of 4F2hc is colored in yellow.

Extended Data Fig. 5 Distributions of human disease mutations.

a, hSGLT1 mutations found in glucose galactose malabsorption human patients are mapped onto the homology structural model of hSGLT1. Cα positions of mutations are shown as purple spheres. hSGLT1 is shown in blue ribbons. b, A 180° rotated view of a. c, hSGLT2 mutations found in familial renal glycosuria patients are mapped onto the structure of hSGLT2. Cα positions of mutations are shown as purple spheres. hSGLT2 is shown in brown ribbons. d, A 180° rotated view of c.

Extended Data Fig. 6 Chemical structures of related compounds.

a, Chemical structures of glucose and its various analogues. Carbons of D-glucose are numbered in blue. The C2-OH and C3-OH groups of glucose that are important for hSGLT2 binding are shown in red dashed circles. b, Chemical structures of representative SGLT2i.

Extended Data Fig. 7 Electron density map of hSGLT2 at the putative sodium-binding site.

a, The electron density map of hSGLT2 is contoured at 1.8 σ. b, a 180° rotated view of a.

Extended Data Fig. 8 The model of hSGLT2 inhibition by SGLT2i.

a, hSGLT2 is shown in blue. MAP17 is shown in red. SGLT2i is shown in green. Glucose is shown in yellow. Sodium ions are shown as purple spheres. b, The cut-open view of hSGLT2 shown with the surface colored in pink. Empagliflozin is shown as green spheres. c, The cut-open view of SERT (PDB ID: 5I73) with the surface colored in brown. (S)-citaloprams are shown as green spheres. d, The cut-open view of DAT (PDB ID: 4M48), with the surface colored in red. Nortriptyline is shown as green spheres.

Extended Data Table 1 Cryo-EM data collection, refinement and validation statistics
Extended Data Table 2 The potencies of empagliflozin on various hSGLT2 constructs

Supplementary information

Supplementary Fig. 1

The uncropped gel of Extended Data Fig. 1e with size marker indicated.

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Niu, Y., Liu, R., Guan, C. et al. Structural basis of inhibition of the human SGLT2–MAP17 glucose transporter. Nature 601, 280–284 (2022).

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