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-Structure paper
タイトル | Structural basis for human Ca1.2 inhibition by multiple drugs and the neurotoxin calciseptine. |
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ジャーナル・号・ページ | Cell, Vol. 186, Issue 24, Page 5363-5374.e16, Year 2023 |
掲載日 | 2023年11月22日 |
![]() | Shuai Gao / Xia Yao / Jiaofeng Chen / Gaoxingyu Huang / Xiao Fan / Lingfeng Xue / Zhangqiang Li / Tong Wu / Yupeng Zheng / Jian Huang / Xueqin Jin / Yan Wang / Zhifei Wang / Yong Yu / Lei Liu / Xiaojing Pan / Chen Song / Nieng Yan / ![]() ![]() |
PubMed 要旨 | Ca1.2 channels play crucial roles in various neuronal and physiological processes. Here, we present cryo-EM structures of human Ca1.2, both in its apo form and in complex with several drugs, as well ...Ca1.2 channels play crucial roles in various neuronal and physiological processes. Here, we present cryo-EM structures of human Ca1.2, both in its apo form and in complex with several drugs, as well as the peptide neurotoxin calciseptine. Most structures, apo or bound to calciseptine, amlodipine, or a combination of amiodarone and sofosbuvir, exhibit a consistent inactivated conformation with a sealed gate, three up voltage-sensing domains (VSDs), and a down VSD. Calciseptine sits on the shoulder of the pore domain, away from the permeation path. In contrast, when pinaverium bromide, an antispasmodic drug, is inserted into a cavity reminiscent of the IFM-binding site in Na channels, a series of structural changes occur, including upward movement of VSD coupled with dilation of the selectivity filter and its surrounding segments in repeat III. Meanwhile, S4-5 merges with S5 to become a single helix, resulting in a widened but still non-conductive intracellular gate. |
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手法 | EM (単粒子) |
解像度 | 2.9 - 3.3 Å |
構造データ | EMDB-29102, PDB-8fhs: EMDB-37472, PDB-8we6: EMDB-37473, PDB-8we7: EMDB-37474, PDB-8we8: EMDB-37475, PDB-8we9: EMDB-37476, PDB-8wea: |
化合物 | ![]() ChemComp-CA: ![]() ChemComp-BBI: ![]() ChemComp-WG6: ![]() ChemComp-3PE: ![]() ChemComp-CLR: ![]() ChemComp-NAG: ![]() ChemComp-PT5: ![]() ChemComp-6UB: ![]() ChemComp-9Z9: ![]() ChemComp-WB9: |
由来 |
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![]() | TRANSPORT PROTEIN / Cav1.2 / Channels / Calcium Ion-Selective / MEMBRANE PROTEIN |