• Crystal structures of Ryanodin...

*Result*: Crystal structures of Ryanodine Receptor reveal dantrolene and azumolene interactions guiding inhibitor development.

Title:
Crystal structures of Ryanodine Receptor reveal dantrolene and azumolene interactions guiding inhibitor development.
Authors:
Hadiatullah, Hadiatullah, Lin, Lianyun, Wang, Zhiyan, Sundarraj, Rajamanikandan, Wang, Qing, Lai, Xinru, Kurebayashi, Nagomi, Kobayashi, Takuya, Yamazawa, Toshiko, Chen, Yu Seby, Wang, Wenlan, Zhao, Hongxia, Yin, Yiqing, Murayama, Takashi, Van Petegem, Filip, Yuchi, Zhiguang
Source:
Nature Communications; 11/18/2025, Vol. 16 Issue 1, p1-12, 12p
Subject Terms:
RYANODINE receptors, CRYSTAL structure, MUSCLE relaxants, AZULENE, DRUG discovery, MOLECULAR interactions, ALLOSTERIC regulation, CHEMICAL inhibitors
Database:
Complementary Index

*Further Information*

*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. This study reports crystal structures of the ryanodine receptor domain bound to dantrolene and azumolene. The work reveals cooperative nucleotide binding and provides structural insights to guide the design of potent inhibitors targeting the receptor. [ABSTRACT FROM AUTHOR]

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