Cryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42

Tao Ma, Lei Wang, Anping Chai, Chao Liu, Wenqiang Cui, Shuguang Yuan, Shannon Wing Ngor Au, Liang Sun, Xiaokang Zhang, Zhenzhen Zhang, Jianping Lu, Yuanzhu Gao, Peiyi Wang, Zhifang Li, Yujie Liang, Horst Vogel (), Yu Tian Wang (), Daping Wang (), Kaige Yan () and Huawei Zhang ()
Additional contact information
Tao Ma: Chinese Academy of Sciences
Lei Wang: Southern University of Science and Technology
Anping Chai: Chinese Academy of Sciences
Chao Liu: Southern University of Science and Technology
Wenqiang Cui: Chinese Academy of Sciences
Shuguang Yuan: Chinese Academy of Sciences
Shannon Wing Ngor Au: The Chinese University of Hong Kong
Liang Sun: Shenzhen Shuli Tech Co., Ltd
Xiaokang Zhang: Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions
Zhenzhen Zhang: Southern University of Science and Technology
Jianping Lu: Shenzhen Mental Health Center
Yuanzhu Gao: Southern University of Science and Technology
Peiyi Wang: Southern University of Science and Technology
Zhifang Li: Southern University of Science and Technology
Yujie Liang: Shenzhen Mental Health Center
Horst Vogel: Chinese Academy of Sciences
Yu Tian Wang: Chinese Academy of Sciences
Daping Wang: Southern University of Science and Technology
Kaige Yan: Southern University of Science and Technology
Huawei Zhang: Chinese Academy of Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-39218-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39218-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-39218-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().