2. Academic Validation
  3. Structural basis of urate transport by glucose transporter 9

Structural basis of urate transport by glucose transporter 9

  • Cell Rep. 2025 Apr 22;44(4):115514. doi: 10.1016/j.celrep.2025.115514.
Daiki Matsushita 1,  Yu Toyoda 2,  Yongchan Lee 1,  Maeda Aoi 1,  Hirotaka Matsuo 3,  Tappei Takada 4,  Tomohiro Nishizawa 5
Affiliations

Affiliations

  • 1 Graduate School of Medical Life Science, Yokohama City University, Yokohama 230-0045, Japan.
  • 2 Department of Pharmacy, The University of Tokyo Hospital, Tokyo 113-8655, Japan; Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa 359-8513, Japan.
  • 3 Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa 359-8513, Japan.
  • 4 Department of Pharmacy, The University of Tokyo Hospital, Tokyo 113-8655, Japan.
  • 5 Graduate School of Medical Life Science, Yokohama City University, Yokohama 230-0045, Japan. Electronic address: t-2438@yokohama-cu.ac.jp.
PMID: 40186864 DOI: 10.1016/j.celrep.2025.115514
Abstract

Glucose transporter 9 (GLUT9) is a critical urate transporter involved in renal reabsorption, playing a pivotal role in regulating physiological urate levels and representing a potential therapeutic target for gout. Despite such clinical significance, the structural basis of urate recognition and transport by GLUT9 remains elusive. Here, we present the cryoelectron microscopy (cryo-EM) structures of GLUT9 in the inward-open conformation in both apo and urate-bound states. Urate binds in a cleft between the N-terminal and C-terminal domains, interacting via hydrogen bonds and hydrophobic interactions. Structural comparison with sugar-transporting GLUTs highlights unique amino acid compositions in the substrate recognition pocket of GLUT9. Functional and mutational studies directly measuring GLUT9-mediated urate uptake further demonstrate the cooperative roles of multiple residues in urate recognition. Our findings elucidate the structural basis of urate transport by GLUT9 and provide valuable insights for the development of uricosuric drugs targeting GLUT9.

Keywords

CP: Molecular biology; GLUT family; GLUT9; SLC2A9; cryo-EM; gout; renal hypouricemia; structure; transporter; urate.

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