Molecular basis of ligand recognition and transport by glucose transporters

Dong Deng, Pengcheng Sun, Chuangye Yan, Meng Ke, Xin Jiang, Lei Xiong, Wenlin Ren, Kunio Hirata, Masaki Yamamoto, Shilong Fan and Nieng Yan ()
Additional contact information
Dong Deng: State Key Laboratory of Membrane Biology, Tsinghua University
Pengcheng Sun: State Key Laboratory of Membrane Biology, Tsinghua University
Chuangye Yan: State Key Laboratory of Membrane Biology, Tsinghua University
Meng Ke: State Key Laboratory of Membrane Biology, Tsinghua University
Xin Jiang: State Key Laboratory of Membrane Biology, Tsinghua University
Lei Xiong: Tsinghua-Peking Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University
Wenlin Ren: State Key Laboratory of Membrane Biology, Tsinghua University
Kunio Hirata: Research Infrastructure Group, SR Life Science Instrumentation Unit, RIKEN/SPring-8 Center
Masaki Yamamoto: Research Infrastructure Group, SR Life Science Instrumentation Unit, RIKEN/SPring-8 Center
Shilong Fan: Center for Structural Biology, Tsinghua University
Nieng Yan: State Key Laboratory of Membrane Biology, Tsinghua University

Nature, 2015, vol. 526, issue 7573, 391-396

Abstract: Abstract The major facilitator superfamily glucose transporters, exemplified by human GLUT1–4, have been central to the study of solute transport. Using lipidic cubic phase crystallization and microfocus X-ray diffraction, we determined the structure of human GLUT3 in complex with d-glucose at 1.5 Å resolution in an outward-occluded conformation. The high-resolution structure allows discrimination of both α- and β-anomers of d-glucose. Two additional structures of GLUT3 bound to the exofacial inhibitor maltose were obtained at 2.6 Å in the outward-open and 2.4 Å in the outward-occluded states. In all three structures, the ligands are predominantly coordinated by polar residues from the carboxy terminal domain. Conformational transition from outward-open to outward-occluded entails a prominent local rearrangement of the extracellular part of transmembrane segment TM7. Comparison of the outward-facing GLUT3 structures with the inward-open GLUT1 provides insights into the alternating access cycle for GLUTs, whereby the C-terminal domain provides the primary substrate-binding site and the amino-terminal domain undergoes rigid-body rotation with respect to the C-terminal domain. Our studies provide an important framework for the mechanistic and kinetic understanding of GLUTs and shed light on structure-guided ligand design.

Date: 2015
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DOI: 10.1038/nature14655

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