EMD-44080

Single-particle
3.7 Å
EMD-44080 Deposition: 13/03/2024
Map released: 18/09/2024
Last modified: 13/11/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-44080

Human urate transporter 1 URAT1 in complex with verinurad

EMD-44080

Single-particle
3.7 Å
EMD-44080 Deposition: 13/03/2024
Map released: 18/09/2024
Last modified: 13/11/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: Human urate transporter 1 in complex with verinurad
Fitted models: 9b1i (Avg. Q-score: 0.405)

Deposition Authors: Dai Y , Lee CH
Transport mechanism and structural pharmacology of human urate transporter URAT1.
Dai Y , Lee CH
(2024) Cell Res , 34 , 776 - 787
PUBMED: 39245778
DOI: doi:10.1038/s41422-024-01023-1
ISSN: 1001-0602
Abstract:
Urate is an endogenous product of purine metabolism in the liver. High urate levels in the blood lead to gout, a very common and painful inflammatory arthritis. Excreted urate is reabsorbed in the kidney mainly by URAT1 antiporter, a key target for anti-gout drugs. To uncover the mechanisms of urate transport and drug inhibition, we determined cryo-EM structures of human URAT1 with urate, counter anion pyrazinoate, or anti-gout drugs of different chemotypes - lesinurad, verinurad, and dotinurad. We captured the outward-to-inward transition of URAT1 during urate uptake, revealing that urate binds in a phenylalanine-rich pocket and engages with key gating residues to drive the transport cycle. In contrast to the single binding site for urate, pyrazinoate interacts with three distinct, functionally relevant sites within URAT1, a mechanism that has not yet been observed in other anion antiporters. In addition, we found that while all three drugs compete with substrates and halt the transport cycle, verinurad and dotinurad further hijack gating residues to achieve high potency. These insights advance our understanding of organic anion transport and provide a foundation for designing improved gout therapeutics.