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| Title | Ligand-induced activation of RyR1 in native membranes. |
|---|---|
| Journal, issue, pages | Nat Commun, Vol. 17, Issue 1, Year 2026 |
| Publish date | Sep 24, 2026 |
 Authors | Vasilii Mikirtumov / Sabrina Golusik / Ruifeng Huo / Thiemo Sprink / Nikita Balyschew / Wen Yang / Christoph Diebolder / Shuguang Yuan / Abhay Kotecha / Mikhail Kudryashev /     |
| PubMed Abstract | Synchronized calcium release through arrays of the ryanodine receptor RyR1, fundamental to skeletal muscle excitation-contraction coupling, is achieved through the mechanical interaction of RyR1s and ...Synchronized calcium release through arrays of the ryanodine receptor RyR1, fundamental to skeletal muscle excitation-contraction coupling, is achieved through the mechanical interaction of RyR1s and voltage-sensing receptors DHPR that activate RyR1s in response to action potentials. The calcium release is enhanced through "coupled gating", when the activation of one channel promotes the opening of its neighbours. Here, we determine high-resolution structures of RyR1 in native sarcoplasmic reticulum membranes by cryo-EM/ET, capturing the conformations along the activation pathway and corner-to-corner interfaces between adjacent RyR1 receptors. Compared with purified RyR1s, receptors in native membranes follow an activation pathway with reduced cytosolic-shell tilt and greater consecutive in-plane rotation. Activation-induced rotation remodels the inter-receptor interface, lowering the energy barrier to the cooperative opening of the receptor cluster. Our analysis demonstrates how the native membrane receptor lattice influences ion channel cluster dynamics and provides a mechanistic framework for understanding calcium signaling in muscle. |
 External links | Nat Commun / PubMed:42786160 / PubMed Central |
| Methods | EM (single particle) / EM (subtomogram averaging) |
| Resolution | 3.2 - 25.97 Å |
| Structure data |  EMDB-54431: Focused map of the N-Terminal cytosolic shell part, Apo-state RyR1 in the native membrane solved by "SPA"  EMDB-54433: Focused map of the BSol cytosolic shell part, Apo-state RyR1 in the native membrane solved by "SPA"  EMDB-54435: Focused map of the CSol activation core part, Apo-state RyR1 in the native membrane solved by "SPA"  EMDB-54437: Focused map of the TMD/TaF/CTD part, Apo-state RyR1 in the native membrane solved by "SPA"  EMDB-54438: Consensus map, Apo-state RyR1 in the native membrane solved by "SPA" EMDB-54445, PDB-9s16:  EMDB-54449: Consensus map, Apo-state RyR1 with ACP in the native membrane  EMDB-54450: Focused map of the N-Terminal cytosolic shell part, Apo-state RyR1 with ACP in the native membrane  EMDB-54451: Focused map of the BSol cytosolic shell part, Apo-state RyR1 with ACP in the native membrane  EMDB-54452: Focused map of the CSol activation core part, Apo-state RyR1 with ACP in the native membrane  EMDB-54453: Focused map of the TMD/TaF/CTD part, Apo-state RyR1 with ACP in the native membrane EMDB-54454, PDB-9s1h:  EMDB-54501: Focused map of the N-Terminal cytosolic shell part, Primed-state RyR1 with calcium in activating concentration in the native membrane  EMDB-54502: Focused map of the BSol cytosolic shell part, Primed-state RyR1 with calcium in activating concentration in the native membrane  EMDB-54503: Focused map of the CSol activation core part, Primed-state RyR1 with calcium in activating concentration in the native membrane  EMDB-54504: Focused map of the TMD/TaF/CTD part, Primed-state RyR1 with calcium in activating concentration in the native membrane  EMDB-54505: Consensus map, Primed-state RyR1 with calcium in activating concentration in the native membrane  EMDB-54507: RyR1-RyR1 dimer map, Primed-state RyR1 with calcium in activating concentration in the native membrane EMDB-54508, PDB-9s2r: EMDB-54509, PDB-9s2s:  EMDB-54512: Focused map of the N-Terminal cytosolic shell part, Primed-state RyR1 with activating ligand mixture (Calcium/ACP/Caffeine) in the native membrane  EMDB-54513: Focused map of the BSol cytosolic shell part, Primed-state RyR1 with activating ligand mixture (Calcium/ACP/Caffeine) in the native membrane  EMDB-54514: Focused map of the CSol activation core part, Primed-state RyR1 with activating ligand mixture (Calcium/ACP/Caffeine) in the native membrane  EMDB-54515: Focused map of the TMD/TaF/CTD part, Primed-state RyR1 with activating ligand mixture (Calcium/ACP/Caffeine) in the native membrane  EMDB-54516: Consensus map, Primed-state RyR1 with activating ligand mixture (Calcium/ACP/Caffeine) in the native membrane  EMDB-54517: RyR1-RyR1 Dimer map with activating ligand mixture (Calcium/ACP/Caffeine) in the native membrane EMDB-54552, PDB-9s3u: EMDB-54553, PDB-9s3v:  EMDB-54554: Focused map of the N-Terminal cytosolic shell part, Activated-state RyR1 with activating ligand mixture (Calcium/ACP/Caffeine) in the native membrane  EMDB-54555: Focused map of the BSol cytosolic shell part, Activated-state RyR1 with activating ligand mixture (Calcium/ACP/Caffeine) in the native membrane  EMDB-54557: Focused map of the CSol activation core part, Activated-state RyR1 with activating ligand mixture (Calcium/ACP/Caffeine) in the native membrane  EMDB-54562: Focused map of the TMD/TaF/CTD part, Activated-state RyR1 with activating ligand mixture (Calcium/ACP/Caffeine) in the native membrane  EMDB-54568: Consensus map, Activated-state RyR1 with activating ligand mixture (Calcium/ACP/Caffeine) in the native membrane EMDB-54569, PDB-9s4l: EMDB-54570, PDB-9s4n:  EMDB-54571: Focused map of the N-Terminal cytosolic shell part, Locked-state RyR1 with ryanodine in the native membrane  EMDB-54572: Focused map of the BSol cytosolic shell part, Locked-state RyR1 with ryanodine in the native membrane  EMDB-54573: Focused map of the CSol activation core part, Locked-state RyR1 with ryanodine in the native membrane  EMDB-54574: Focused map of the TMD/TaF/CTD part, Locked-state RyR1 with ryanodine in the native membrane  EMDB-54575: Consensus map, Locked-state RyR1 with ryanodine in the native membrane  EMDB-54580: RyR1-RyR1 Dimer map with ryanodine in the native membrane  EMDB-54587: Focused Map of the Activation core and TMD parts, Apo-state RyR1 in the native membrane solved by StA EMDB-54588, PDB-9s54:  EMDB-54589: Focused map of the N-Terminal cytosolic shell part, Apo-state RyR1 in the native membrane solved by StA EMDB-54590, PDB-9s55:  EMDB-54592: Consensus map, Apo-state RyR1 in the native membrane solved by StA EMDB-54593, PDB-9s5a: EMDB-54594, PDB-9s5c: EMDB-54595, PDB-9s5e:  EMDB-54596: RyR1-RyR1 dimer map, Apo-state RyR1 in the native membrane solved by StA EMDB-54597, PDB-9s5f:  EMDB-54598: Focused map of the TMD/TaF/CTD part, Primed-state RyR1 with activating ligand mixture (Calcium/ACP/Caffeine) in the native membrane solved by StA  EMDB-54600: Focused map of the CSol activation core part, Primed-state RyR1 with activating ligand mixture (Calcium/ACP/Caffeine) in the native membrane solved by StA  EMDB-54601: Focused map of the BSol cytosolic shell part, Primed-state RyR1 with activating ligand mixture (Calcium/ACP/Caffeine) in the native membrane solved by StA  EMDB-54611: Focused map of the N-Terminal cytosolic shell part, Primed-state RyR1 with activating ligand mixture (Calcium/ACP/Caffeine) in the native membrane solved by StA  EMDB-54612: Consensus map, Primed-state RyR1 with activating ligand mixture (Calcium/ACP/Caffeine) in the native membrane solved by StA  EMDB-54614: RyR1-RyR1 Dimer map, Primed-state RyR1 with activating ligand mixture (Calcium/ACP/Caffeine) in the native membrane solved by StA EMDB-54615, PDB-9s5w: EMDB-54616, PDB-9s5y: EMDB-54617, PDB-9s5z: |
| Chemicals |  ChemComp-POV:  ChemComp-ZN:  ChemComp-ACP:  ChemComp-CA:  ChemComp-CFF: |
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 Keywords | MEMBRANE PROTEIN / ryanodine receptor type 1 / ryr1 / skeletal muscle / sarcoplasmic reticulum / SR / native membrane |
oryctolagus cuniculus (rabbit)