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

Hadiatullah Hadiatullah, Lianyun Lin, Zhiyan Wang, Rajamanikandan Sundarraj, Qing Wang, Xinru Lai, Nagomi Kurebayashi, Takuya Kobayashi, Toshiko Yamazawa, Yu Seby Chen, Wenlan Wang, Hongxia Zhao, Yiqing Yin, Takashi Murayama, Filip Van Petegem and Zhiguang Yuchi ()
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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

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-65096-1

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