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Ryanodine receptors(RyRs)mediate rapid release of calcium ions from sarcoplasmic/endoplasmic reticulum and play a pivotal role in the excitation-contraction coupling of skeletal and cardiac muscles.RyRs represent the largest known ion channels and are homotetramers,with each subunit comprising approximately five thousand residues.We determined the structure of the full-length rabbit RyR1 in complex with the modulator FKBP12 at an overall resolution of 3.8(A),using single particle electron cryomicroscopy.Near-atomic resolution is achieved at the channel domain and its adjoining domains in the cytoplasmic region and resolves 70 percent of the 2.2 million Dalton molecular mass of RyR1.The carboxyl terminal fragment(residues 4545-5037)exhibits the voltage-gated ion channel(VGIC)superfamily fold.An outer site formed by the side chains of Asp4899/Glu4900 and an inner site surrounded by carbonyl oxygen atoms may serve as the Ca2+binding sites along the selectivity filter(SF)vestibule.A highly electronegative hairpin loop connecting S5 and the pore helix is positioned above the entrance to the SF vestibule.The four elongated S6 segments form a right-handed helical bundle that closes the ion-conducting pore at the cytoplasmic border of the membrane.The cytoplasmic vestibule of the pore is enriched with Glu and Asp residues,which likely modulate ion conductance.The S6 segment is followed by a carboxyl-terminal domain(CTD)which contains a previously uncharacterized zinc finger motif.The sequences between S2 and S3 segments fold into a cytoplasmic domain which we name the VSC domain.In addition to the channel domain,structural models were built for three previously uncharacterized major domains: the Central domain,the Handle domain,and the Helical domain.These three domains,all displaying the armadillo repeat fold,together with the amino-terminal domain,constitute a network of superhelical scaffold at the cytoplasmic side.Allosteric regulation of the pore is mediated by the Central domains,which directly interact with the CTD and VSC domains.These structural features explain high ion conductance by RyRs and allosteric regulation of pore conductance through conformational changes in the cytoplasmic domains.