| Title | Cryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42 |
| Author | 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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| Corresponding Author | Vogel，Horst; Wang，Yu Tian; Wang，Daping; Yan，Kaige; Zhang，Huawei |
| Joint first author | Ma，Tao; Wang，Lei; Chai，Anping |
| Publication Years | 2023-12-01
|
| DOI | |
| Source Title | |
| EISSN | 2041-1723
|
| Volume | 14Issue:1 |
| Abstract | 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. |
| URL | [Source Record] |
| Indexed By | |
| Language | English
|
| Important Publications | NI Journal Papers
; NI论文
|
| SUSTech Authorship | 共同第一
; Corresponding
|
| Funding Project | 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]
|
| WOS Research Area | Science & Technology - Other Topics
|
| WOS Subject | Multidisciplinary Sciences
|
| WOS Accession No | WOS:001026289800044
|
| Publisher | |
| Scopus EID | 2-s2.0-85163073431
|
| Data Source | Scopus
|
| Citation statistics |
Cited Times [WOS]:1
|
| Document Type | Journal Article |
| Identifier | http://kc.sustech.edu.cn/handle/2SGJ60CL/559465 |
| Department | Department of Biomedical Engineering 生命科学学院 冷冻电镜中心 |
| Affiliation | 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 |
| First Author Affilication | Department of Biomedical Engineering |
| Corresponding Author Affilication | Department of Biomedical Engineering; School of Life Sciences |
| Recommended Citation 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).
|
| 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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