Structural basis for urate recognition and apigenin inhibition of human GLUT9

Zilin Shen, Li Xu, Tong Wu, Huan Wang, Qifan Wang, Xiaofei Ge, Fang Kong, Gaoxingyu Huang and Xiaojing Pan ()
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Zilin Shen: Tsinghua University
Li Xu: Shenzhen Medical Academy of Research and Translation (SMART)
Tong Wu: Tsinghua University
Huan Wang: Tsinghua University
Qifan Wang: Tsinghua University
Xiaofei Ge: Tsinghua University
Fang Kong: Tsinghua University
Gaoxingyu Huang: Westlake University
Xiaojing Pan: Shenzhen Medical Academy of Research and Translation (SMART)

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract Urate, the physiological form of uric acid and a potent antioxidant in serum, plays a pivotal role in scavenging reactive oxygen species. Yet excessive accumulation of urate, known as hyperuricemia, is the primary risk factor for the development of gout. The high-capacity urate transporter GLUT9 represents a promising target for gout treatment. Here, we present cryo-electron microscopy structures of human GLUT9 in complex with urate or its inhibitor apigenin at overall resolutions of 3.5 Å and 3.3 Å, respectively. In both structures, GLUT9 exhibits an inward open conformation, wherein the substrate binding pocket faces the intracellular side. These structures unveil the molecular basis for GLUT9’s substrate preference of urate over glucose, and show that apigenin acts as a competitive inhibitor by occupying the substrate binding site. Our findings provide critical information for the development of specific inhibitors targeting GLUT9 as potential therapeutics for gout and hyperuricemia.

Date: 2024
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DOI: 10.1038/s41467-024-49420-9

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