Structural basis for urate recognition and apigenin inhibition of human GLUT9.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
12 Jun 2024
12 Jun 2024
Historique:
received:
18
01
2024
accepted:
03
06
2024
medline:
13
6
2024
pubmed:
13
6
2024
entrez:
12
6
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38866775
doi: 10.1038/s41467-024-49420-9
pii: 10.1038/s41467-024-49420-9
doi:
Substances chimiques
Glucose Transport Proteins, Facilitative
0
SLC2A9 protein, human
0
Uric Acid
268B43MJ25
Apigenin
7V515PI7F6
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
5039Subventions
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 32322039
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 32271252
Organisme : Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)
ID : 2022YFA1206400
Informations de copyright
© 2024. The Author(s).
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