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Crystal structures of Ryanodine Receptor reveal dantrolene and azumolene interactions guiding inhibitor development

Author

Listed:
  • Hadiatullah Hadiatullah

    (Tianjin University)

  • Lianyun Lin

    (Tianjin University)

  • Zhiyan Wang

    (Tianjin Medical University Cancer Institute & Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy; Tianjin’s Clinical Research Center for Cancer)

  • Rajamanikandan Sundarraj

    (Tianjin University)

  • Qing Wang

    (Tianjin University)

  • Xinru Lai

    (Tianjin University)

  • Nagomi Kurebayashi

    (Juntendo University School of Medicine)

  • Takuya Kobayashi

    (Juntendo University School of Medicine)

  • Toshiko Yamazawa

    (The Jikei University School of Medicine)

  • Yu Seby Chen

    (University of British Columbia)

  • Wenlan Wang

    (Tianjin University)

  • Hongxia Zhao

    (Tianjin University)

  • Yiqing Yin

    (Tianjin Medical University Cancer Institute & Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy; Tianjin’s Clinical Research Center for Cancer)

  • Takashi Murayama

    (Juntendo University School of Medicine)

  • Filip Van Petegem

    (University of British Columbia)

  • Zhiguang Yuchi

    (Tianjin University
    Tianjin Medical University Cancer Institute & Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy; Tianjin’s Clinical Research Center for Cancer
    Haihe Laboratory of Sustainable Chemical Transformations
    Chinese Academy of Agricultural Sciences)

Abstract

The ryanodine receptor (RyR) is a critical drug target, yet dantrolene (DAN) remains the only FDA-approved inhibitor, limited by hepatotoxicity and unsuitable for chronic use. To guide improved inhibitor development, we determine high-resolution crystal structures of the RyR Repeat12 (R12) domain bound to DAN, its analog azumolene (AZU), and adenine nucleotides (AMP-PCP or ADP). DAN/AZU and nucleotides bind cooperatively to a pseudosymmetric cleft, with key interactions involving Trp880 and Trp994. Binding induces a clamshell-like closure of the R12 domain. Isothermal titration calorimetry (ITC) reveals higher affinity in the presence of nucleotides and lower affinity for RyR2 due to nearby substitutions. Structural comparison with cryo-EM data suggests that DAN/AZU binding allosterically influences RyR gating and functional regulation. Structure-based screening identifies a potent compound targeting the same site but with a distinct binding mode. Our findings highlight the power of domain-focused crystallography in guiding RyR inhibitor discovery and overcoming cryo-EM resolution limitations.

Suggested Citation

  • Hadiatullah Hadiatullah & Lianyun Lin & Zhiyan Wang & Rajamanikandan Sundarraj & Qing Wang & Xinru Lai & Nagomi Kurebayashi & Takuya Kobayashi & Toshiko Yamazawa & Yu Seby Chen & Wenlan Wang & Hongxia, 2025. "Crystal structures of Ryanodine Receptor reveal dantrolene and azumolene interactions guiding inhibitor development," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65096-1
    DOI: 10.1038/s41467-025-65096-1
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    References listed on IDEAS

    as
    1. Marco C. Miotto & Steven Reiken & Anetta Wronska & Qi Yuan & Haikel Dridi & Yang Liu & Gunnar Weninger & Carl Tchagou & Andrew R. Marks, 2024. "Structural basis for ryanodine receptor type 2 leak in heart failure and arrhythmogenic disorders," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Takuya Kobayashi & Akihisa Tsutsumi & Nagomi Kurebayashi & Kei Saito & Masami Kodama & Takashi Sakurai & Masahide Kikkawa & Takashi Murayama & Haruo Ogawa, 2022. "Molecular basis for gating of cardiac ryanodine receptor explains the mechanisms for gain- and loss-of function mutations," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Zhiguang Yuchi & Siobhan M. Wong King Yuen & Kelvin Lau & Ainsley Q. Underhill & Razvan L. Cornea & James D. Fessenden & Filip Van Petegem, 2015. "Crystal structures of ryanodine receptor SPRY1 and tandem-repeat domains reveal a critical FKBP12 binding determinant," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
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