Structural basis for urate recognition and apigenin inhibition of human GLUT9

• Published in: Nature communications Vol. 15; no. 1; pp. 5039 - 10
• Main Authors: Shen, Zilin, Xu, Li, Wu, Tong, Wang, Huan, Wang, Qifan, Ge, Xiaofei, Kong, Fang, Huang, Gaoxingyu, Pan, Xiaojing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.06.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 42/109; 42/70; 631/45/535/1258/1259; 631/45/612/1237; 631/535; 82/80; 82/83; 9/74; Antioxidants; Apigenin - chemistry; Apigenin - pharmacology; Binding Sites; Conformation; Cryoelectron Microscopy; Drug development; Electron microscopy; Glucose Transport Proteins, Facilitative - antagonists & inhibitors; Glucose Transport Proteins, Facilitative - chemistry; Glucose Transport Proteins, Facilitative - metabolism; Gout; Gout - drug therapy; Gout - metabolism; HEK293 Cells; Humanities and Social Sciences; Humans; Hyperuricemia; Hyperuricemia - drug therapy; Hyperuricemia - metabolism; Inhibitors; Models, Molecular; multidisciplinary; Protein Binding; Reabsorption; Reactive oxygen species; Rheumatism; Risk factors; Scavenging; Science; Science (multidisciplinary); Substrate inhibition; Substrate preferences; Substrates; Uric acid; Uric Acid - chemistry; Uric Acid - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49420-9

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. Uric acid is a serum antioxidant, but excess can cause gout. Authors investigated GLUT9, crucial for urate reabsorption, and determined its structure with urate and apigenin providing insight for substrate preference and rational drug design.