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Molecular mechanism of drug inhibition of URAT1

Author

Listed:
  • Zhuoya Yu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Tuo Hu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jiawei Su

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jun Zhao

    (Shandong Laboratory of Advanced Agricultural Sciences at Weifang)

  • Renjie Li

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Qiao Ma

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Qihao Chen

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Qinru Bai

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yanli Dong

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Pu Yuan

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Na Li

    (National Clinical Research Center for Cardiovascular Diseases)

  • Xuejun Cai Zhang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yan Zhao

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

Abstract

Hyperuricemia, characterized by elevated serum urate levels, is a key factor in the pathogenesis of gout. URAT1 is essential for renal urate reabsorption and has emerged as a critical therapeutic target for managing hyperuricemia. However, the precise transport mechanism and the inhibitory effects of uricosuric drugs on URAT1 remain unclear. Here, we present structures of the double-mutant rat homolog of URAT1 in complex with its substrate urate, and the clinical drugs benzbromarone, lesinurad, verinurad, and sulfinpyrazone. The urate-bound structure elucidates key residues involved in recognizing urate, while the structures bound with drugs clearly demonstrate the distinct binding mode of each drug with URAT1. These drugs stabilize URAT1’s inward-facing state, blocking conformational transitions. Additionally, critical interactions essential for its conformational transition are identified. These findings provide a molecular framework for understanding the physiological function of URAT1 and for developing more efficacious therapies to treat hyperuricemia.

Suggested Citation

  • Zhuoya Yu & Tuo Hu & Jiawei Su & Jun Zhao & Renjie Li & Qiao Ma & Qihao Chen & Qinru Bai & Yanli Dong & Pu Yuan & Na Li & Xuejun Cai Zhang & Yan Zhao, 2025. "Molecular mechanism of drug inhibition of URAT1," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61226-x
    DOI: 10.1038/s41467-025-61226-x
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    References listed on IDEAS

    as
    1. Basavraj Khanppnavar & Julian Maier & Freja Herborg & Ralph Gradisch & Erika Lazzarin & Dino Luethi & Jae-Won Yang & Chao Qi & Marion Holy & Kathrin Jäntsch & Oliver Kudlacek & Klaus Schicker & Thomas, 2022. "Structural basis of organic cation transporter-3 inhibition," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Atsushi Enomoto & Hiroaki Kimura & Arthit Chairoungdua & Yasuhiro Shigeta & Promsuk Jutabha & Seok Ho Cha & Makoto Hosoyamada & Michio Takeda & Takashi Sekine & Takashi Igarashi & Hirotaka Matsuo & Yu, 2002. "Molecular identification of a renal urate–anion exchanger that regulates blood urate levels," Nature, Nature, vol. 417(6887), pages 447-452, May.
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