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TitleMolecular basis of the urate transporter URAT1 inhibition by gout drugs.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 5178, Year 2025
Publish dateJun 4, 2025
AuthorsYang Suo / Justin G Fedor / Han Zhang / Kalina Tsolova / Xiaoyu Shi / Kedar Sharma / Shweta Kumari / Mario Borgnia / Peng Zhan / Wonpil Im / Seok-Yong Lee /
PubMed AbstractHyperuricemia is a condition when uric acid, a waste product of purine metabolism, accumulates in the blood. Untreated hyperuricemia can lead to crystal formation of monosodium urate in the joints, ...Hyperuricemia is a condition when uric acid, a waste product of purine metabolism, accumulates in the blood. Untreated hyperuricemia can lead to crystal formation of monosodium urate in the joints, causing a painful inflammatory disease known as gout. These conditions are associated with many other diseases and affect a significant and increasing proportion of the population. The human urate transporter 1 (URAT1) is responsible for the reabsorption of ~90% of uric acid in the kidneys back into the blood, making it a primary target for treating hyperuricemia and gout. Despite decades of research and development, clinically available URAT1 inhibitors have limitations because the molecular basis of URAT1 inhibition by gout drugs remains unknown. Here we present cryo-electron microscopy structures of URAT1 alone and in complex with three clinically relevant inhibitors: benzbromarone, lesinurad, and the recently developed compound TD-3. Together with functional experiments and molecular dynamics simulations, we reveal that these inhibitors bind selectively to URAT1 in inward-open states. Furthermore, we discover differences in the inhibitor-dependent URAT1 conformations as well as interaction networks, which contribute to drug specificity. Our findings illuminate a general theme for URAT1 inhibition, paving the way for the design of next-generation URAT1 inhibitors in the treatment of gout and hyperuricemia.
External linksNat Commun / PubMed:40467597 / PubMed Central
MethodsEM (single particle)
Resolution2.55 - 3.0 Å
Structure data

46948

9dk9

EMDB-46948, PDB-9dk9:
Structure of URAT1 with no external ligand added
Method: EM (single particle) / Resolution: 2.68 Å

46949

9dka

EMDB-46949, PDB-9dka:
Structure of URAT1 in complex with benzbromarone
Method: EM (single particle) / Resolution: 3.0 Å

46950

9dkb

EMDB-46950, PDB-9dkb:
Structure of URAT1 in complex with lesinurad
Method: EM (single particle) / Resolution: 2.74 Å

46951

9dkc

EMDB-46951, PDB-9dkc:
Structure of URAT1 in complex with TD-3
Method: EM (single particle) / Resolution: 2.55 Å

Chemicals

ChemComp-R75:
[3,5-bis(bromanyl)-4-oxidanyl-phenyl]-(2-ethyl-1-benzofuran-3-yl)methanone / antiarrhythmic, inhibitor*YM

PDB-1ail:
N-TERMINAL FRAGMENT OF NS1 PROTEIN FROM INFLUENZA A VIRUS

PDB-1a45:
GAMMAF CRYSTALLIN FROM BOVINE LENS

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / Membrane protein / membrane transporter

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