Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Structural basis of glucose-6-phosphate transport by human SLC37A2

Nature Structural & Molecular Biology volume 33, pages 112–122 (2026)Cite this article

Subjects

Abstract

Glucose-6-phosphate (G6P) transporters are crucial for glucose metabolism by mediating G6P transport from the cytoplasm to endoplasmic reticulum (ER). However, their transport mechanisms remain poorly understood. Here, we elucidate the structural and functional basis of human solute carrier family 37 member 2 (SLC37A2), a G6P transporter implicated in metabolic regulation and macrophage inflammation. We show that SLC37A2 functions as a uniporter, facilitating G6P transport independent of inorganic phosphate gradients. Structures of SLC37A2 in the apo and G6P-bound states reveal a dimeric architecture. Both the ER luminal-open and cytosolic-open structures are captured, showing the structural dynamics during G6P transport. G6P is coordinated by SLC37A2 through interactions with its phosphate and hydroxyl groups. Furthermore, mapping mutations associated with glycogen storage disease type Ib onto SLC37A2 highlights residues essential for transport activity. Together, this work provides structural insights into G6P transport and establishes a framework for understanding related metabolic disorders.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Characterization of G6P transport by SLC37A2 and SLC37A4.
Fig. 2: Structures of SLC37A2 determined in the apo state and in the presence of G6P.
Fig. 3: G6P coordination of SLC37A2.
Fig. 4: Conformational dynamics of SLC37A2 during G6P transport.

Similar content being viewed by others

Data availability

Model coordinates and cryo-EM density maps for the apo, luminal-open state SLC37A2apo, LO, the G6P-unbound, luminal-open state SLC37A2G6P, LO, the G6P-bound cytosolic-open state SLC37A2G6P, CO and the asymmetric state SLC37A2G6P, LO+CO were deposited to the PDB under accession codes 9UCM, 9UDX, 9UDW and 9UDV and the EM Data Bank under accession codes EMD-64048, EMD-64074, EMD-64073 and EMD-64072, respectively. Data and materials can be obtained from the corresponding authors upon request. Source data are provided with this paper.

References

  1. Rajas, F., Gautier-Stein, A. & Mithieux, G. Glucose-6 phosphate, a central hub for liver carbohydrate metabolism. Metabolites 9, 282 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lizák, B. et al. Glucose transport and transporters in the endomembranes. Int. J. Mol. Sci. 20, 5898 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Marcolongo, P. et al. Multiple roles of glucose-6-phosphatases in pathophysiology: state of the art and future trends. Biochim. Biophys. Acta 1830, 2608–2618 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Arion, W. J., Walls, B. K., Lange, A. J. & Ballas, L. M. On the involvement of a glucose 6-phosphate transport system in the function of microsomal glucose 6-phosphatase. Mol. Cell. Biochem. 6, 75–83 (1975).

    Article  CAS  PubMed  Google Scholar 

  5. Csala, M. et al. Transport and transporters in the endoplasmic reticulum. Biochim. Biohpys. Acta 1768, 1325–1341 (2007).

    Article  CAS  Google Scholar 

  6. Gerin, I., Veiga-da-Cunha, M., Achouri, Y., Collet, J. F. & Van Schaftingen, E. Sequence of a putative glucose 6-phosphate translocase, mutated in glycogen storage disease type Ib. FEBS Lett. 419, 235–238 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. Hiraiwa, H., Pan, C. J., Lin, B. C., Moses, S. W. & Chou, J. Y. Inactivation of the glucose 6-phosphate transporter causes glycogen storage disease type 1b. J. Biol. Chem. 274, 5532–5536 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Chou, J. Y., Jun, H. S. & Mansfield, B. C. Type I glycogen storage diseases: disorders of the glucose-6-phosphatase/glucose-6-phosphate transporter complexes. J. Inherit. Metab. Dis. 38, 511–519 (2015).

    Article  CAS  PubMed  Google Scholar 

  9. Annabi, B. et al. The gene for glycogen-storage disease type 1b maps to chromosome 11q23. Am. J. Hum. Genet. 62, 400–405 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ihara, K., Nomura, A., Hikino, S., Takada, H. & Hara, T. Quantitative analysis of glucose-6-phosphate translocase gene expression in various human tissues and haematopoietic progenitor cells. J. Inherit. Metab. Dis. 23, 583–592 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Arion, W. J., Carlson, P. W., Lange, A. J. & Wallin, B. K. The specificity of glucose 6-phosphatase of intact liver microsomes. J. Biol. Chem. 247, 2558–2565 (1972).

    Article  CAS  PubMed  Google Scholar 

  12. Arion, W. J., Ballas, L. M., Lange, A. J. & Wallin, B. K. Microsomal membrane permeability and the hepatic glucose-6-phosphatase system. Interactions of system with D-Mannose 6-phosphate and D-mannose. J. Biol. Chem. 251, 4891–4897 (1976).

    Article  CAS  PubMed  Google Scholar 

  13. Arion, W. J., Lange, A. J., Walls, H. E. & Ballas, L. M. Evidence for the participation of independent translocases for phosphate and glucose-6-phosphate in the microsomal glucose-6-phosphatase system. Interactions of the System with orthophosphate, inorganic pyrophosphate, and carbamyl-phosphate. J. Biol. Chem. 255, 10396–10406 (1980).

    Article  CAS  PubMed  Google Scholar 

  14. Cappello, A. R., Curcio, R., Lappano, R., Maggiolini, M. & Dolce, V. The physiopathological role of the exchangers belonging to the SLC37 family. Front. Chem. 6, 122 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Shieh, J. J., Pan, C. J., Mansfield, B. C. & Chou, J. Y. A glucose-6-phosphate hydrolase, widely expressed outside the liver, can explain age-dependent resolution of hypoglycemia in glycogen storage disease type Ia. J. Biol. Chem. 278, 47098–47103 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Chou, J. Y., Cho, J. H., Kim, G. Y. & Mansfield, B. C. Molecular biology and gene therapy for glycogen storage disease type Ib. J. Inherit. Metab. Dis. 41, 1007–1014 (2018).

    Article  CAS  PubMed  Google Scholar 

  17. Sim, S. W., Weinstein, D. A., Lee, Y. M. & Jun, H. S. Glycogen storage disease type Ib: role of glucose-6-phosphate transporter in cell metabolism and function. FEBS Lett. 594, 3–18 (2020).

    Article  CAS  PubMed  Google Scholar 

  18. Chen, L. Y., Lin, B. C., Pan, C. J., Hiraiwa, H. & Chou, J. Y. Structural requirements for the stability and microsomal transport activity of the human glucose 6-phosphate transporter. J. Biol. Chem. 275, 34280–34286 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Chen, L. Y., Pan, C. J. & Chou, J. Y. Structure-function analysis of the glucose-6-phosphate transporter deficient in glycogen storage disease type Ib. Hum. Mol. Genet. 11, 3199–3207 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Pan, C. J. et al. The signature motif in human glucose-6-phosphate transporter is essential for microsomal transport of glucose-6-phosphate. Hum. Genet. 112, 430–433 (2003).

    Article  PubMed  Google Scholar 

  21. Ahn, H. H. et al. Identification of glucose-6-phosphate transporter as a key regulator functioning at the autophagy initiation step. FEBS Lett. 589, 2100–2109 (2015).

    Article  CAS  PubMed  Google Scholar 

  22. Jeon, Y. G., Kim, Y. Y., Lee, G. & Kim, J. B. Physiological and pathological roles of lipogenesis. Nat. Metab. 5, 735–759 (2023).

    Article  CAS  PubMed  Google Scholar 

  23. Chou, J. Y., Jun, H. S. & Mansfield, B. C. Glycogen storage disease type I and G6Pase-β deficiency: etiology and therapy. Nat. Rev. Endocrinol. 6, 676–688 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Belkaid, A., Copland, I. B., Massillon, D. & Annabi, B. Silencing of the human microsomal glucose-6-phosphate translocase induces glioma cell death: potential new anticancer target for curcumin. FEBS Lett. 580, 3746–3752 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Pao, S. S., Paulsen, I. T. & Saier, M. H. Major facilitator superfamily. Microbiol. Mol. Biol. Rev. 62, 1–34 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bartoloni, L. & Antonarakis, S. E. The human sugar-phosphate/phosphate exchanger family SLC37. Pflugers Arch. 447, 780–783 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Chou, J. Y. & Mansfield, B. C. The SLC37 family of sugar-phosphate/phosphate exchangers. Curr. Top. Membr. 73, 357–382 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kim, J. Y., Tillison, K., Zhou, S., Wu, Y. & Smas, C. M. The major facilitator superfamily member Slc37a2 is a novel macrophage- specific gene selectively expressed in obese white adipose tissue. Am. J. Physiol. Endocrinol. Metab. 293, E110–E120 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Wang, Z. et al. Solute carrier family 37 member 2 (SLC37A2) negatively regulates murine macrophage inflammation by controlling glycolysis. iScience 23, 101125 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhao, Q. et al. Hematopoietic cell-specific SLC37A2 deficiency accelerates atherosclerosis in LDL receptor-deficient mice. Front. Cardiovasc. Med. 8, 777098 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ng, P. Y. et al. Sugar transporter Slc37a2 regulates bone metabolism in mice via a tubular lysosomal network in osteoclasts. Nat. Commun. 14, 906 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wilfinger, J. et al. Primary vitamin D receptor target genes as biomarkers for the vitamin D3 status in the hematopoietic system. J. Nutr. Biochem. 25, 875–884 (2014).

    Article  CAS  PubMed  Google Scholar 

  33. Saksa, N. et al. Dissecting high from low responders in a vitamin D3 intervention study. J. Steroid Biochem. Mol. Biol. 148, 275–282 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. Iskarpatyoti, J. A. et al. Mast cell regranulation requires a metabolic switch involving mTORC1 and a glucose-6-phosphate transporter. Cell Rep. 40, 111346 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Villani, A. et al. Clearance by microglia depends on packaging of phagosomes into a unique cellular compartment. Dev. Cell 49, 77–88.e7 (2019).

    Article  CAS  PubMed  Google Scholar 

  36. Zilberstein, D. et al. SLC37A1 and SLC37A2 are phosphate-linked, glucose-6-phosphate a. PLoS ONE 6, e23157 (2011).

    Article  Google Scholar 

  37. Chen, S.-Y. et al. The glucose-6-phosphate transporter is a phosphate-linked antiporter deficient in glycogen storage disease type Ib and Ic. FASEB J. 22, 2206–2213 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Marcolongo, P. et al. The glucose-6-phosphate transport is not mediated by a glucose-6-hosphate/phosphate exchange in liver microsomes. FEBS Lett. 586, 3354–3359 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Arion, W. J. et al. Chlorogenic acid and hydroxynitrobenzaldehyde: new inhibitors of hepatic glucose 6-phosphatase. Arch. Biochem. Biophys. 339, 315–322 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Pan, C. J., Lin, B. C. & Chou, J. Y. Transmembrane topology of human glucose 6-phosphate transporter. J. Biol. Chem. 274, 13865–13869 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Yan, N. Structural biology of the major facilitator superfamily transporters. Annu. Rev. Biophys. 44, 257–283 (2015).

    Article  CAS  PubMed  Google Scholar 

  42. Kumari, M., Balaji, P. V. & Sunoj, R. B. Quantification of binding affinities of essential sugars with a tryptophan analogue and the ubiquitous role of C–H···π interactions. Phys. Chem. Chem. Phys. 13, 6517–6530 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Sun, L. F. et al. Crystal structure of a bacterial homologue of glucose transporters GLUT1-4. Nature 490, 361–366 (2012).

    Article  CAS  PubMed  Google Scholar 

  44. Deng, D. et al. Molecular basis of ligand recognition and transport by glucose transporters. Nature 526, 391–396 (2015).

    Article  CAS  PubMed  Google Scholar 

  45. Qureshi, A. A. et al. The molecular basis for sugar import in malaria parasites. Nature 578, 321–325 (2020).

    Article  CAS  PubMed  Google Scholar 

  46. Bavnhoj, L., Paulsen, P. A., Flores-Canales, J. C., Schiott, B. & Pedersen, B. P. Molecular mechanism of sugar transport in plants unveiled by structures of glucose/H+ symporter STP10. Nat. Plants 7, 1409–1419 (2021).

    Article  PubMed  Google Scholar 

  47. Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bavnhoj, L. et al. Structure and sucrose binding mechanism of the plant SUC1 sucrose transporter. Nat. Plants 9, 938–950 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Paulsen, P. A., Custódio, T. F. & Pedersen, B. P. Crystal structure of the plant symporter STP10 illuminates sugar uptake mechanism in monosaccharide transporter superfamily. Nat. Commun. 10, 407 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ying, W. et al. Structure and function of the Arabidopsis ABC transporter ABCB19 in brassinosteroid export. Science 383, eadj4591 (2024).

    Article  CAS  PubMed  Google Scholar 

  51. Yang, Z. S. et al. Structural insights into auxin recognition and efflux by PIN1. Nature 609, 611–615 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Punjani, A., Rubinstein, J. L., Fleet, D. J. & Brubaker, M. A. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat. Methods 14, 290–296 (2017).

    Article  CAS  PubMed  Google Scholar 

  53. Rosenthal, P. B. & Henderson, R. Optimal determination of particle orientation, absolute hand, and contrast loss in single-particle electron cryomicroscopy. J. Mol. Biol. 333, 721–745 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Chen, S. X. et al. High-resolution noise substitution to measure overfitting and validate resolution in 3D structure determination by single particle electron cryomicroscopy. Ultramicroscopy 135, 24–35 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Pettersen, E. F. et al. UCSF chimera—a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D 66, 486–501 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D 66, 213–221 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the Cryo-EM Center of the University of Science and Technology of China for the EM facility support. This work was supported by the National Natural Science Foundation of China (32471279 to X.L. and 32322041, 32321001 and W2412029 to L.S.), the Scientific Research Innovation Capability Support Project for Young Faculty (ZYGXQNJSKYCXNLZCXM-B8 to L.S.), Center for Advanced Interdisciplinary Science and Biomedicine of IHM (QYPY20230034 to L.S.), Natural Science Foundation of Anhui Province (2408085JX005 to L.S.), Fundamental Research Funds for the Central Universities (WK9100000031 to L.S. and WK9100000065 to Z.Y.) and USTC Research Funds of the Double First-Class Initiative (YD9100002004 to L.S. and YD9100002020 to X.L.). L.S. is supported by the Outstanding Young Scholar Award from the Qiu Shi Science and Technologies Foundation. X.L. and L.S. are supported by the Young Scholar Award from the Cyrus Tang Foundation.

Author information

Author notes

  1. These authors contributed equally: Qinxuan Lai, Mengzhen Xu.

Authors and Affiliations

  1. Department of Neurology, The First Affiliated Hospital of USTC, MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

    Qinxuan Lai, Mengzhen Xu, Yongxiang Gao, Zhisen Yang, Linfeng Sun & Xin Liu

  2. Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China

    Qinxuan Lai, Mengzhen Xu, Yongxiang Gao, Zhisen Yang, Linfeng Sun & Xin Liu

  3. Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, China

    Qinxuan Lai, Mengzhen Xu, Yongxiang Gao, Linfeng Sun & Xin Liu

Authors
  1. Qinxuan Lai
    View author publications

    Search author on:PubMed Google Scholar

  2. Mengzhen Xu
    View author publications

    Search author on:PubMed Google Scholar

  3. Yongxiang Gao
    View author publications

    Search author on:PubMed Google Scholar

  4. Zhisen Yang
    View author publications

    Search author on:PubMed Google Scholar

  5. Linfeng Sun
    View author publications

    Search author on:PubMed Google Scholar

  6. Xin Liu
    View author publications

    Search author on:PubMed Google Scholar

Contributions

X.L. and L.S. conceptualized the project. X.L. and L.S. designed the experiments and analyzed the data. Q.L. and M.X. performed the molecular cloning and protein purification work. Q.L., M.X. and Z.Y. performed the transport assays. Q.L., Z.Y. and Y.G. performed the cryo-EM data collection. Q.L. and Z.Y. performed the cryo-EM data processing and model building. Q.L., L.S. and X.L. wrote the manuscript. All authors revised the manuscript.

Corresponding authors

Correspondence to Zhisen Yang, Linfeng Sun or Xin Liu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Structural & Molecular Biology thanks the anonymous reviewers for their contribution to the peer review of this work. Peer reviewer reports are available. Primary Handling Editor: Katarzyna Ciazynska, in collaboration with the Nature Structural & Molecular Biology team.

Additional information

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

Extended data

Extended Data Fig. 1 Sequence alignment and phylogenetic tree plotting for SLC37 family members.

a, Sequence alignment of Homo sapiens SLC37A1, SLC37A2, SLC37A3, and SLC37A4. The transmembrane (TM) domains, H0, and H13 helixes of SLC37A2 are indicated above the sequences. The G6P interacting residues are indicated above the sequences with stars (★). The natural mutation sites in SLC37A4 associated with diseases are indicated below the sequences with asterisks (＊). b, The percent identity matrix of the human SLC37 family transporters. Sequence identities were calculated using the alignment tool in UniProt (https://www.uniprot.org/align). c, Phylogenetic tree of human SLC37 family members constructed with the program iTOL v7 (https://itol.embl.de/). Protein sequences of SLC37A1 (UniProt ID: P57057), SLC37A2 (UniProt ID: Q8TED4), SLC37A3 (UniProt ID: Q8NCC5), SLC37A4 (UniProt ID: O43826) were acquired from UniProt (https://www.uniprot.org/).

Extended Data Fig. 2 Protein purification and transport analyses of SLC37A2 and SLC37A4.

a, The size exclusion chromatography (SEC) profiles of wild-type SLC37A2 and SLC37A4 (SLC37A2WT and SLC37A4WT) purified from HEK293F cells, and the SEC profiles of SLC37A2WT and the N-terminal truncation mutant (1-13 aa) SLC37A2ΔN expressed in HEK293F cells. b, PNGase F treatment results of SLC37A2WT, SLC37A2ΔN, SLC37A4WT proteins. The representative SDS-PAGE result of the proteins prior to and after PNGase F treatment is shown here. The experiments were repeated independently at least three times with similar results. c, G6P transport activities of SLC37A2WT and SLC37A4WT assessed using a proteoliposome-based 3H-G6P transport assay with phosphate buffer (50 mM KH2PO4, pH 7.0, 1 mM DTT, and the protease cocktails) as the inner buffer and MOPS/K buffer (20 mM MOPS, pH 7.5, 75 mM K2SO4, 2.5 mM MgSO4, 1 mM DTT, and the protease cocktails) as the exterior buffer. The data are presented as mean ± SD (n = 3 biologically independent repeats). Significances of the SLC37A2 and SLC37A4 groups versus the control group were determined using a two-tailed unpaired t-test. **** P < 0.0001. The other exact P value was labeled above the column. d, Glucose transport activities of the SLC37A2WT and SLC37A4WT proteins assessed via a proteoliposome-based 3H-glucose transport assay in which HEPES/Na buffer (25 mM HEPES, pH 7.4, 150 mM NaCl) was used as the interior and exterior buffer. The data are presented as the mean ± SD (n = 3 biologically independent repeats). Significances of the SLC37A2 and SLC37A4 groups versus the control group were determined using a two-tailed unpaired t-test. The exact P values were labeled above the columns. e, Chemical structures of chlorogenic acid (CHA), vanadate and inorganic phosphate (Pi). f, Chemical structures of the sugars and sugar phosphates used in the 3H-G6P competition assay.

Source data

Extended Data Fig. 3 Cryo-EM analyses of SLC37A4apo and SLC37A2apo.

a, A typical cryo-EM micrograph of SLC37A4 in the apo state (SLC37A4apo). 4078 micrographs were obtained with similar results. b, Representative 2D classification images of SLC37A4apo. c, The low-resolution cryo-EM map resolved for SLC37A4apo. d, A typical cryo-EM micrograph of SLC37A2 in the apo state (SLC37A2apo). 1903 micrographs were obtained with similar results. e, Selected fine 2D classification images of SLC37A2apo. f, Local resolution map of SLC37A2apo. g, Gold-standard Fourier shell correlation curves for the overall EM map of SLC37A2apo. h, Euler angle distributions of SLC37A2apo.

Extended Data Fig. 4 Flowchart for the data processing of SLC37A2 in the apo state and the structural analyses of SLC37A2.

a, Flowchart for the data processing SLC37A2 in the apo state (SLC37A2apo). b, EM densities of the twelve transmembrane helices of the SLC37A2apo, LO map. Residues with notable side chains are labelled. c, Structural superposition of the N-domain and C-domain of SLC37A2 structure. d, Characteristic MFS-fold observed in the SLC37A2 structure.

Extended Data Fig. 5 Cryo-EM analyses of SLC37A2 in the presence of G6P.

a, A typical cryo-EM micrograph of SLC37A2 in the presence of G6P (SLC37A2G6P). 3170 micrographs were obtained with similar results. b, Representative 2D classification images of SLC37A2G6P. c, Local resolution map of SLC37A2G6P, LO. d, Gold-standard Fourier shell correlation curves for the overall map of SLC37A2G6P, LO. e, Euler angle distributions of SLC37A2G6P, LO. f, Local resolution map of SLC37A2G6P, CO. g, Gold-standard Fourier shell correlation curves for the overall map of SLC37A2G6P, CO. h, Euler angle distributions of SLC37A2G6P, CO. i, Local resolution map of SLC37A2G6P, LO+CO. j, Gold-standard Fourier shell correlation curves for the overall map of SLC37A2G6P, LO+CO. k, Euler angle distributions of SLC37A2G6P, LO+CO.

Extended Data Fig. 6 Flowchart for the data processing of SLC37A2 in the presence of G6P.

Details can be found in the imaging processing section in Methods.

Extended Data Fig. 7 EM densities of the transmembrane helices in the symmetric SLC37A2G6P, LO and SLC37A2G6P, CO maps.

a, EM densities of the twelve transmembrane helices of the symmetric SLC37A2G6P, LO map. Residues with notable side chains are labelled aside. b, EM densities of the twelve transmembrane helices of the symmetric SLC37A2G6P, CO map. Residues with notable side chains are labelled aside.

Extended Data Fig. 8 EM densities of the transmembrane helices in the asymmetric SLC37A2G6P, LO+CO map.

a, EM density maps of the twelve transmembrane helices of the ER luminal-open protomer in the asymmetric SLC37A2G6P, LO+CO structure. Residues with notable side chains are labelled aside. b, EM density maps of the twelve transmembrane helices of the cytosolic-open protomer in the asymmetric SLC37A2G6P, LO+CO structure. Residues with notable side chains are labelled aside.

Extended Data Fig. 9 Sugar binding site in SLC37A2 and structural mapping of the SLC37A4 mutations related to human GSD-Ib disease.

a, Sugar binding site in SLC37A2 and the sugar transporter homologues of the MFS superfamily. The N-domain and C-domain of SLC37A2 and the sugar transporter homologues are in different colours. The bound G6P and glucose (Glc) molecules are shown in sticks. The PDB accession codes are indicated for the homologue structures. b, Structural superposition of glucose-bound human GLUT3 (hGLUT3) and G6P-bound SLC37A2. c, Missense mutations in SLC37A4 that cause human GSD-Ib disease mapped to the predicted SLC37A4 structure using AlphaFold2 and the corresponding mutations in the determined G6P-bound SLC37A2 structure. Mutations are shown in slate spheres. Conserved sites within SLC37A4 and SLC37A2 are coloured white. Conserved sites involved in G6P binding in SLC37A2G6P, CO are coloured red. d, 3H-G6P transport by SLC37A2WT and selected mutants corresponding to those in SLC37A4 which are associated with GSD-Ib disease. Net 3H-G6P accumulations of the mutants calculated by deleting the 3H-G6P accumulation of the control group were normalized to the net accumulation of SLC37A2WT. Data are means ± SD (n = 3 biologically independent repeats). Significances of the mutants versus wild-type (WT) were evaluated using one-way ANOVA with Dunnett’s multiple comparisons test. **** P < 0.0001. e, Side-view of the mutations corresponding to those disease-related residues in SLC37A2 near the G6P binding site in SLC37A2G6P, CO. f, Top-view of the mutations corresponding to those disease-related residues in SLC37A2 near the G6P binding site in SLC37A2G6P, CO. g, G403 residue in the SLC37A2 luminal- and cytosolic-open conformations.

Source data

Supplementary information

Source data

Source Data Fig. 1

Statistical source data.

Source Data Fig. 2

Statistical source data.

Source Data Fig. 3

Statistical source data.

Source Data Fig. 4

Statistical source data.

Source Data Extended Data Fig. 2

Unprocessed gel.

Source Data Extended Data Fig. 2

Statistical source data.

Source Data Extended Data Fig. 9

Statistical source data.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lai, Q., Xu, M., Gao, Y. et al. Structural basis of glucose-6-phosphate transport by human SLC37A2. Nat Struct Mol Biol 33, 112–122 (2026). https://doi.org/10.1038/s41594-025-01712-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41594-025-01712-4

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing