9LS7
The crystal structure of human RyR3 Repeat12 domain complex with RI-2 and AMP-PCP
This is a non-PDB format compatible entry.
Summary for 9LS7
| Entry DOI | 10.2210/pdb9ls7/pdb |
| Descriptor | Ryanodine receptor 3, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, (2~{S})-4-(naphthalen-2-ylamino)-4-oxidanylidene-2-(3-oxidanylpropylamino)butanoic acid, ... (4 entities in total) |
| Functional Keywords | repeat12 domain, dantranlene, amp-pcp, ryanodine receptor, membrane protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 101617.47 |
| Authors | Hadiatullah, H.,Lin, L.,Yuchi, Z. (deposition date: 2025-02-04, release date: 2025-10-22, Last modification date: 2026-05-06) |
| Primary citation | Hadiatullah, H.,Lin, L.,Wang, Z.,Sundarraj, R.,Wang, Q.,Lai, X.,Kurebayashi, N.,Kobayashi, T.,Yamazawa, T.,Chen, Y.S.,Wang, W.,Zhao, H.,Yin, Y.,Murayama, T.,Van Petegem, F.,Yuchi, Z. Crystal structures of Ryanodine Receptor reveal dantrolene and azumolene interactions guiding inhibitor development. Nat Commun, 16:10110-10110, 2025 Cited by PubMed 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. PubMed: 41253812DOI: 10.1038/s41467-025-65096-1 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.49 Å) |
Structure validation
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