| 题名 | Cryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42 |
| 作者 | Ma，Tao1,2  ; Wang，Lei3; Chai，Anping4,5; Liu，Chao2; Cui，Wenqiang1,6; Yuan，Shuguang1; Wing Ngor Au，Shannon7; Sun，Liang8; Zhang，Xiaokang5,9,10; Zhang，Zhenzhen2; Lu，Jianping11; Gao，Yuanzhu12; Wang，Peiyi12; Li，Zhifang2; Liang，Yujie11; Vogel，Horst1,13 ; Wang，Yu Tian4,10; Wang，Daping2,14; Yan，Kaige3; Zhang，Huawei1,2
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| 通讯作者 | Vogel，Horst; Wang，Yu Tian; Wang，Daping; Yan，Kaige; Zhang，Huawei |
| 共同第一作者 | Ma，Tao; Wang，Lei; Chai，Anping |
| 发表日期 | 2023-12-01
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| DOI | |
| 发表期刊 | |
| EISSN | 2041-1723
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| 卷号 | 14期号:1 |
| 摘要 | ClC-2 transports chloride ions across plasma membranes and plays critical roles in cellular homeostasis. Its dysfunction is involved in diseases including leukodystrophy and primary aldosteronism. AK-42 was recently reported as a specific inhibitor of ClC-2. However, experimental structures are still missing to decipher its inhibition mechanism. Here, we present cryo-EM structures of apo ClC-2 and its complex with AK-42, both at 3.5 Å resolution. Residues S162, E205 and Y553 are involved in chloride binding and contribute to the ion selectivity. The side-chain of the gating glutamate E205 occupies the putative central chloride-binding site, indicating that our structure represents a closed state. Structural analysis, molecular dynamics and electrophysiological recordings identify key residues to interact with AK-42. Several AK-42 interacting residues are present in ClC-2 but not in other ClCs, providing a possible explanation for AK-42 specificity. Taken together, our results experimentally reveal the potential inhibition mechanism of ClC-2 inhibitor AK-42. |
| 相关链接 | [Scopus记录] |
| 收录类别 | |
| 语种 | 英语
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| 重要成果 | NI论文
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| 学校署名 | 共同第一
; 通讯
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| 资助项目 | National Natural Science Foundation of China-Yunnan Joint Fund[31900046]
; National Natural Science Foundation of China-Yunnan Joint Fund[32161133022]
; National Natural Science Foundation of China-Yunnan Joint Fund[32271251]
; National Natural Science Foundation of China-Yunnan Joint Fund[81972085]
; National Natural Science Foundation of China-Yunnan Joint Fund[82172465]
; National Natural Science Foundation of China-Yunnan Joint Fund[82201315]
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| WOS研究方向 | Science & Technology - Other Topics
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| WOS类目 | Multidisciplinary Sciences
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| WOS记录号 | WOS:001026289800044
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| 出版者 | |
| Scopus记录号 | 2-s2.0-85163073431
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| 来源库 | Scopus
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| 引用统计 |
被引频次[WOS]：4
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| 成果类型 | 期刊论文 |
| 条目标识符 | http://sustech.caswiz.com/handle/2SGJ60CL/559465 |
| 专题 | 工学院_生物医学工程系 生命科学学院 冷冻电镜中心 |
| 作者单位 | 1.Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen,518055,China 2.Department of Biomedical Engineering,Southern University of Science and Technology,Shenzhen,518055,China 3.School of Life Sciences,Southern University of Science and Technology,Shenzhen,518055,China 4.Shenzhen Key Laboratory of Translational Research for Brain Diseases,The Brain Cognition and Brain Disease Institute,Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen,China 5.Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions,Shenzhen,Guangdong,518055,China 6.University of Chinese Academy of Sciences,Beijing,China 7.School of Life Sciences,The Chinese University of Hong Kong,Shatin,Hong Kong 8.Shenzhen Shuli Tech Co.,Ltd,Shenzhen,Guangdong,518126,China 9.Interdisciplinary Center for Brain Information,The Brain Cognition and Brain Disease Institute,Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen,Guangdong,518055,China 10.Faculty of Life and Health Sciences,Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen,Guangdong,518055,China 11.Department of Child and Adolescent Psychiatry,Shenzhen Kangning Hospital,Shenzhen Mental Health Center,Shenzhen,518020,China 12.Cryo-EM Facility Center,Southern University of Science and Technology,Shenzhen,Guangdong,518055,China 13.Institut des Sciences et Ingénierie Chimiques (ISIC),Ecole Polytechnique Fédérale de Lausanne (EPFL),Lausanne,Switzerland 14.Department of Orthopedics,Shenzhen Intelligent Orthopaedics and Biomedical Innovation Platform,Guangdong Provincial Research Center for Artificial Intelligence and Digital Orthopedic Technology,Shenzhen Second People’s Hospital,The First Affiliated Hospital of Shenzhen University,Shenzhen,518000,China |
| 第一作者单位 | 生物医学工程系 |
| 通讯作者单位 | 生物医学工程系; 生命科学学院 |
| 推荐引用方式 GB/T 7714 |
Ma，Tao,Wang，Lei,Chai，Anping,et al. Cryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42[J]. Nature Communications,2023,14(1).
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| APA |
Ma，Tao.,Wang，Lei.,Chai，Anping.,Liu，Chao.,Cui，Wenqiang.,...&Zhang，Huawei.(2023).Cryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42.Nature Communications,14(1).
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| MLA |
Ma，Tao,et al."Cryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42".Nature Communications 14.1(2023).
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