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7T64

Rabbit RyR1 disease mutant Y523S in complex with FKBP12.6 embedded in lipidic nanodisc in the closed state

This is a non-PDB format compatible entry.
Summary for 7T64
Entry DOI10.2210/pdb7t64/pdb
EMDB information25709
DescriptorRyanodine receptor 1, Peptidyl-prolyl cis-trans isomerase FKBP1B, ZINC ION (3 entities in total)
Functional Keywordsryanodine receptor, ryr, ryr1, calcium channel, mutation, ntdc mutation, malignant hyperthermia, central core disease, membrane protein, excitation-contraction coupling
Biological sourceOryctolagus cuniculus (rabbit)
More
Total number of polymer chains8
Total formula weight2310261.10
Authors
Iyer, K.A.,Hu, Y.,Murayama, T.,Samso, M. (deposition date: 2021-12-13, release date: 2022-07-20, Last modification date: 2024-02-28)
Primary citationIyer, K.A.,Hu, Y.,Klose, T.,Murayama, T.,Samso, M.
Molecular mechanism of the severe MH/CCD mutation Y522S in skeletal ryanodine receptor (RyR1) by cryo-EM.
Proc.Natl.Acad.Sci.USA, 119:e2122140119-e2122140119, 2022
Cited by
PubMed Abstract: Ryanodine receptors (RyRs) are main regulators of intracellular Ca release and muscle contraction. The Y522S mutation of RyR1 causes central core disease, a weakening myopathy, and malignant hyperthermia, a sudden and potentially fatal response to anesthetics or heat. Y522 is in the core of the N-terminal subdomain C of RyR1 and the mechanism of how this mutation orchestrates malfunction is unpredictable for this 2-MDa ion channel, which has four identical subunits composed of 15 distinct cytoplasmic domains each. We expressed and purified the RyR1 rabbit homolog, Y523S, from HEK293 cells and reconstituted it in nanodiscs under closed and open states. The high-resolution cryogenic electron microscopic (cryo-EM) three-dimensional (3D) structures show that the phenyl ring of Tyr functions in a manner analogous to a "spacer" within an α-helical bundle. Mutation to the much smaller Ser alters the hydrophobic network within the bundle, triggering rearrangement of its α-helices with repercussions in the orientation of most cytoplasmic domains. Examining the mutation-induced readjustments exposed a series of connected α-helices acting as an ∼100 Å-long lever: One end protrudes toward the dihydropyridine receptor, its molecular activator (akin to an antenna), while the other end reaches the Ca activation site. The Y523S mutation elicits channel preactivation in the absence of any activator and full opening at 1.5 µM free Ca, increasing by ∼20-fold the potency of Ca to activate the channel compared with RyR1 wild type (WT). This study identified a preactivated pathological state of RyR1 and a long-range lever that may work as a molecular switch to open the channel.
PubMed: 35867837
DOI: 10.1073/pnas.2122140119
PDB entries with the same primary citation
Experimental method
ELECTRON MICROSCOPY (4 Å)
Structure validation

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