Recent advances in determining the three-dimensional architecture of the skeletal muscle ryanodine receptor/calcium release channel (RyR) by cryo-electron microscopy and three-dimensional reconstruction are discussed. The tetrameric receptor is characterized by a large 4-fold symmetric cytoplasmic assembly that consists of many domains separated by solvent-containing crevices and holes. Experimental evidence suggests that at least one regulatory ligand, calmodulin, binds to sites on the cytoplasmic assembly that are at least 10 nanometers from the transmembrane channel.
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