Effective muscle contraction relies on synchronized opening of RyR1 calcium channels. Here, authors present high-resolution structures of RyR1 in native membranes, revealing how ligand-induced activat...

We isolated junctional SR microsomes from rabbit skeletal muscle and examined RyR1 arrays by cryo-ET (Fig. 1a), following the previous reports20,21,23,24 with modifications, and performed high-resolution imaging of the SR vesicles in 3D by cryo-ET and in 2D for single-particle cryo-EM. While the linear two-row organization of the receptors in the muscle was perturbed, the local order was preserved with the corner-to-corner contacts clearly visible (Supplementary Fig. 1). The corner-to-corner contacts were formed via bridging-solenoid BSol domains, recapitulating the physiological arrangement of RyR1. Using a combination of SPA and StA, we determined multiple RyR1 structures under the following conditions: resting (Apo) states with and without the non-hydrolyzable ATP analog adenylyl-imidodiphosphate, denoted ACP; a Primed state induced by activating [free Ca2+] (ActCa); a mixture of Primed and Activated states in equilibrium by the addition of Ca2+, ACP, and caffeine (ActMix); and a Ryanodine-locked state with a fully dilated pore. The reconstructions had global resolutions between 3.5 Å and 4.9 Å (Supplementary Table 1). Focused refinement further improved local resolutions up to 3.0 Å in the most ordered regions, enabling building atomic models (Fig. 1b, Supplementary Figs. 2–10) and confident placement of side chains, bound ligands, and ordered lipids (Fig. 1c–f). Structural...

Using cryo-electron microscopy, the Kudryashev lab has revealed how muscle cell calcium channels open synchronously. The findings, published in “Nature Communications,” may explain a mechanism behind ...

S48168 (ARM210) demonstrated favorable safety, tolerability, and PK, in RYR1-RM affected individuals. Most participants who received 200 mg/day S48168 (ARM210) reported decreased fatigue, a key sympto...

Here the authors report the RyR1 calcium channel structure bound to rosuvastatin: rosuvastatin occupies the same binding site as simvastatin to activate the channel. This may provide a structural basi...

We are excited to announce our latest release! This update is highly recommended. It fixes an issue with pharmcat_pipeline where it uses the original input VCF instead of the preprocessed VCF if it is given a directory instead of a file. Data highlights * PharmVar: new alleles were released for CYP2C9, CYP2D6, CYP3A4, CYP3A5, NUDT15 * ClinPGx: * updates released/published for the CPIC Guideline for RYR1, CACNA1S and Volatile anesthetic agents and Succinylcholine and the CPIC Guideline f

Around 10 percent of people who take statins to lower cholesterol experience mysterious muscle pains, causing many to discontinue these potentially life-saving medicines.

The Drosophila ryanodine receptor plays a conserved role in setting functional and structural muscle properties, regulates embryonic muscle development and could be used to assess the impact of human...

The Drosophila ryanodine receptor plays a conserved role in setting functional and structural muscle properties, regulates embryonic muscle development and could be used to assess the impact of human RYR1 mutations.

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