Structure of the rabbit ryanodine receptor RyR1 at near-atomic resolution. Author Zhen Yan, Xiaochen Bai, Chuangye Yan, Jianping Wu, Zhangqiang Li, Tian Xie, Wei Peng, Changcheng Yin, Xueming Li, Sjors Scheres, Yigong Shi, Nieng Yan Publication Year 2015 Type Journal Article Abstract The ryanodine receptors (RyRs) are high-conductance intracellular Ca(2+) channels that play a pivotal role in the excitation-contraction coupling of skeletal and cardiac muscles. RyRs are the largest known ion channels, with a homotetrameric organization and approximately 5,000 residues in each protomer. Here we report the structure of the rabbit RyR1 in complex with its modulator FKBP12 at an overall resolution of 3.8 Å, determined by single-particle electron cryomicroscopy. Three previously uncharacterized domains, named central, handle and helical domains, display the armadillo repeat fold. These domains, together with the amino-terminal domain, constitute a network of superhelical scaffold for binding and propagation of conformational changes. The channel domain exhibits the voltage-gated ion channel superfamily fold with distinct features. A negative-charge-enriched hairpin loop connecting S5 and the pore helix is positioned above the entrance to the selectivity-filter vestibule. The four elongated S6 segments form a right-handed helical bundle that closes the pore at the cytoplasmic border of the membrane. Allosteric regulation of the pore by the cytoplasmic domains is mediated through extensive interactions between the central domains and the channel domain. These structural features explain high ion conductance by RyRs and the long-range allosteric regulation of channel activities. Keywords Animals, Models, Molecular, Protein Structure, Tertiary, Algorithms, Rabbits, Protein Multimerization, Cryoelectron Microscopy, Allosteric Regulation, Zinc Fingers, Ion Channel Gating, Ryanodine Receptor Calcium Release Channel, Molecular Weight, Sarcoplasmic Reticulum, Tacrolimus Binding Protein 1A Journal Nature Volume 517 Issue 7532 Pages 50-55 Date Published 2015 Jan 01 ISSN Number 1476-4687 DOI 10.1038/nature14063 Alternate Journal Nature PMCID PMC4338550 PMID 25517095 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML