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Crystal structure of the human glucose transporter GLUT1

Nature 510, 121–125 (05 June 2014) | Download Citation

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Abstract

The glucose transporter GLUT1 catalyses facilitative diffusion of glucose into erythrocytes and is responsible for glucose supply to the brain and other organs. Dysfunctional mutations may lead to GLUT1 deficiency syndrome, whereas overexpression of GLUT1 is a prognostic indicator for cancer. Despite decades of investigation, the structure of GLUT1 remains unknown. Here we report the crystal structure of human GLUT1 at 3.2 Å resolution. The full-length protein, which has a canonical major facilitator superfamily fold, is captured in an inward-open conformation. This structure allows accurate mapping and potential mechanistic interpretation of disease-associated mutations in GLUT1. Structure-based analysis of these mutations provides an insight into the alternating access mechanism of GLUT1 and other members of the sugar porter subfamily. Structural comparison of the uniporter GLUT1 with its bacterial homologue XylE, a proton-coupled xylose symporter, allows examination of the transport mechanisms of both passive facilitators and active transporters.

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Accessions

Primary accessions

Protein Data Bank

Data deposits

The X-ray crystallographic coordinates and structure factor files of human GLUT1(N45T/E329Q) have been deposited in the Protein Data Bank (PDB) with the accession code 4PYP.

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Acknowledgements

We thank J. He, L. Tang, F. Yu and S. Huang at Shanghai Synchrotron Radiation Facility (SSRF). This work was supported by funds from the Ministry of Science and Technology (grant number 2011CB910501), Projects 31321062-20131319400, 31125009 and 91017011 of the National Natural Science Foundation of China, and funds from Tsinghua-Peking Center for Life Sciences. The research of N.Y. was supported in part by an International Early Career Scientist grant from the Howard Hughes Medical Institute.

Author information

    • Dong Deng
    • , Chao Xu
    • , Pengcheng Sun
    •  & Jianping Wu

    These authors contributed equally to this work.

Affiliations

  1. State Key Laboratory of Bio-membrane and Membrane Biotechnology, Tsinghua University, Beijing 100084, China

    • Dong Deng
    • , Chao Xu
    • , Pengcheng Sun
    • , Jianping Wu
    • , Chuangye Yan
    • , Mingxu Hu
    •  & Nieng Yan

  2. Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China

    • Dong Deng
    • , Chao Xu
    • , Pengcheng Sun
    • , Jianping Wu
    • , Chuangye Yan
    • , Mingxu Hu
    •  & Nieng Yan

  3. Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China

    • Dong Deng
    • , Chao Xu
    • , Jianping Wu
    • , Mingxu Hu
    •  & Nieng Yan

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Contributions

N.Y. conceived the project. D.D. and N.Y. designed all experiments. D.D., C.X., P.S., J.W., C.Y. and M.H. performed the experiments. All authors analysed the data and contributed to manuscript preparation. N.Y. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Nieng Yan.

Extended data

Extended data figures

  1. 1.

    Structure determination of GLUT1.

  2. 2.

    One β-NG molecule occupies the substrate-binding site of the inward-open GLUT1.

  3. 3.

    Interactions between the N and C domains observed in the inward-open GLUT1 and the outward-facing XylE.

  4. 4.

    Conformational differences between GLUT1 and XylE.

  5. 5.

    Sequence alignment of GLUT1-4 with XylE.

Extended data tables

  1. 1.

    Statistics of data collection and refinement for GLUT1

  2. 2.

    Summary of disease-related sequence variations of GLUT1

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DOI

https://doi.org/10.1038/nature13306

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