@article{2acfb240e9c442dfba1eeff3764b8633,
title = "Molecular basis for allosteric regulation of the type 2 ryanodine receptor channel gating by key modulators",
abstract = "The type 2 ryanodine receptor (RyR2) is responsible for releasing Ca2+ from the sarcoplasmic reticulum of cardiomyocytes, subsequently leading to muscle contraction. Here, we report 4 cryo-electron microscopy (cryo-EM) structures of porcine RyR2 bound to distinct modulators that, together with our published structures, provide mechanistic insight into RyR2 regulation. Ca2+ alone induces a contraction of the central domain that facilitates the dilation of the S6 bundle but is insufficient to open the pore. The small-molecule agonist PCB95 helps Ca2+ to overcome the barrier for opening. FKBP12.6 induces a relaxation of the central domain that decouples it from the S6 bundle, stabilizing RyR2 in a closed state even in the presence of Ca2+ and PCB95. Although the channel is open when PCB95 is replaced by caffeine and adenosine 5′-triphosphate (ATP), neither of the modulators alone can sufficiently counter the antagonistic effect to open the channel. Our study marks an important step toward mechanistic understanding of the sophisticated regulation of this key channel whose aberrant activity engenders life-threatening cardiac disorders.",
keywords = "Allosteric regulation, Cryo-EM structures, Modulators, Type 2 ryanodine receptor",
author = "Ximin Chi and Deshun Gong and Kang Ren and Gewei Zhou and Gaoxingyu Huang and Jianlin Lei and Qiang Zhou and Nieng Yan",
note = "Funding Information: ACKNOWLEDGMENTS. We thank Xiaomin Li (Tsinghua University) for technical support during EM image acquisition. We thank the Tsinghua University Branch of the China National Center for Protein Sciences (Beijing) for providing the cryo-EM facility support. We are thankful for the computational facility support on the cluster of the Bio-Computing Platform (Tsinghua University Branch of the China National Center for Protein Sciences, Beijing) and the “Explorer 100” cluster system of Tsinghua National Laboratory for Information Science and Technology. This work was funded by the National Natural Science Foundation of China (projects 31621092, 31630017, 31930059, 81920108015, and 81861138009) and the National Key R&D Program (Grant 2016YFA0500402) and the National Key Basic Research (973) Program (Grant 2015CB910101) from the Ministry of Science and Technology of China. N.Y. is supported by the Shirley M. Tilghman endowed professorship from Princeton University. Funding Information: We thank Xiaomin Li (Tsinghua University) for technical support during EM image acquisition. We thank the Tsinghua University Branch of the China National Center for Protein Sciences (Beijing) for providing the cryo-EM facility support. We are thankful for the computational facility support on the cluster of the Bio-Computing Platform (Tsinghua University Branch of the China National Center for Protein Sciences, Beijing) and the ?Explorer 100? cluster system of Tsinghua National Laboratory for Information Science and Technology. This work was funded by the National Natural Science Foundation of China (projects 31621092, 31630017, 31930059, 81920108015, and 81861138009) and the National Key R&D Program (Grant 2016YFA0500402) and the National Key Basic Research (973) Program (Grant 2015CB910101) from the Ministry of Science and Technology of China. N.Y. is supported by the Shirley M. Tilghman endowed professorship from Princeton University. Publisher Copyright: {\textcopyright} 2019 National Academy of Sciences. All rights reserved.",
year = "2019",
month = dec,
day = "17",
doi = "10.1073/pnas.1914451116",
language = "English (US)",
volume = "116",
pages = "25575--25582",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "51",
}