@article{c18fce08efba4e6a832375d8fdae14ee,
title = "Molecular Basis for Ligand Modulation of a Mammalian Voltage-Gated Ca2+ Channel",
abstract = "The L-type voltage-gated Ca2+ (Cav) channels are modulated by various compounds exemplified by 1,4-dihydropyridines (DHP), benzothiazepines (BTZ), and phenylalkylamines (PAA), many of which have been used for characterizing channel properties and for treatment of hypertension and other disorders. Here, we report the cryoelectron microscopy (cryo-EM) structures of Cav1.1 in complex with archetypal antagonistic drugs, nifedipine, diltiazem, and verapamil, at resolutions of 2.9 {\AA}, 3.0 {\AA}, and 2.7 {\AA}, respectively, and with a DHP agonist Bay K 8644 at 2.8 {\AA}. Diltiazem and verapamil traverse the central cavity of the pore domain, directly blocking ion permeation. Although nifedipine and Bay K 8644 occupy the same fenestration site at the interface of repeats III and IV, the coordination details support previous functional observations that Bay K 8644 is less favored in the inactivated state. These structures elucidate the modes of action of different Cav ligands and establish a framework for structure-guided drug discovery. A view on how both agonists and antagonists interact with a voltage-gated calcium channel opens up avenues for understanding channel gating and new ligand design.",
keywords = "Bay K 8644, Ca 1.1, Ca agonist, Ca antagonist, cryo-EM structure, dihydropyridine, diltiazem, nifedipine, verapamil, voltage-gated calcium channels",
author = "Yanyu Zhao and Gaoxingyu Huang and Jianping Wu and Qiurong Wu and Shuai Gao and Zhen Yan and Jianlin Lei and Nieng Yan",
note = "Funding Information: We thank Min Yang and Xiangbo Wei (Tsinghua University) for the technical assistance during sample preparation and Xiaomin Li (Tsinghua University) for technical support during EM image acquisition. We thank Dr. Qiang Zhou (Westlake University) and Xiao Fan (Tsinghua University) for advice on EM data processing. We thank Hannah A. Ledford (Princeton University) for critical reading of the manuscript. We thank the Tsinghua University Branch of China National Center for Protein Sciences (Beijing) for providing the cryo-EM facility support. We thank the computational facility support on the cluster of Bio-Computing Platform (Tsinghua University Branch of 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 Key R&D Program ( 2016YFA0500402 ) and the National Key Basic Research (973) Program ( 2015CB910101 ) from Ministry of Science and Technology of China and the National Natural Science Foundation of China (projects 31621092 , 31630017 , and 81861138009 ) N.Y. is supported by the Shirley M. Tilghman endowed professorship from Princeton University . Funding Information: We thank Min Yang and Xiangbo Wei (Tsinghua University) for the technical assistance during sample preparation and Xiaomin Li (Tsinghua University) for technical support during EM image acquisition. We thank Dr. Qiang Zhou (Westlake University) and Xiao Fan (Tsinghua University) for advice on EM data processing. We thank Hannah A. Ledford (Princeton University) for critical reading of the manuscript. We thank the Tsinghua University Branch of China National Center for Protein Sciences (Beijing) for providing the cryo-EM facility support. We thank the computational facility support on the cluster of Bio-Computing Platform (Tsinghua University Branch of 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 Key R&D Program (2016YFA0500402) and the National Key Basic Research (973) Program (2015CB910101) from Ministry of Science and Technology of China and the National Natural Science Foundation of China (projects 31621092, 31630017, and 81861138009) N.Y. is supported by the Shirley M. Tilghman endowed professorship from Princeton University. N.Y. conceived the project. J.W. Y.Z. and G.H. designed all experiments and N.Y. supervised the project. Y.Z. G.H. J.W. Q.W. S.G. Z.Y. and J.L. conducted the experiments. All authors contributed to data analysis. N.Y. J.W. and Y.Z. wrote the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = may,
day = "30",
doi = "10.1016/j.cell.2019.04.043",
language = "English (US)",
volume = "177",
pages = "1495--1506.e12",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "6",
}