Structures of human SGLT in the occluded state reveal conformational changes during sugar transport

  • Nat Commun. 2023 May 22;14(1):2920. doi: 10.1038/s41467-023-38720-1.
Wenhao Cui  #  1  2 ,  Yange Niu  #  1  2 ,  Zejian Sun  3  4 ,  Rui Liu  1  2 ,  Lei Chen  5  6  7
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, 100871, Beijing, China.
  • 2. National Biomedical Imaging Center, Peking University, 100871, Beijing, China.
  • 3. Academy for Advanced Interdisciplinary Studies, Peking University, 100871, Beijing, China.
  • 4. Peking-Tsinghua Center for Life Sciences, Peking University, 100871, Beijing, China.
  • 5. State Key Laboratory of Membrane Biology, College of Future Technology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, 100871, Beijing, China. [email protected].
  • 6. National Biomedical Imaging Center, Peking University, 100871, Beijing, China. [email protected].
  • 7. Peking-Tsinghua Center for Life Sciences, Peking University, 100871, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 37217492 DOI: 10.1038/s41467-023-38720-1
Abstract

Sodium-Glucose Cotransporters (SGLT) mediate the uphill uptake of extracellular sugars and play fundamental roles in sugar metabolism. Although their structures in inward-open and outward-open conformations are emerging from structural studies, the trajectory of how SGLTs transit from the outward-facing to the inward-facing conformation remains unknown. Here, we present the cryo-EM structures of human SGLT1 and SGLT2 in the substrate-bound state. Both structures show an occluded conformation, with not only the extracellular gate but also the intracellular gate tightly sealed. The sugar substrate are caged inside a cavity surrounded by TM1, TM2, TM3, TM6, TM7, and TM10. Further structural analysis reveals the conformational changes associated with the binding and release of substrates. These structures fill a gap in our understanding of the structural mechanisms of SGLT transporters.