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TitleCryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 3424, Year 2023
Publish dateJun 9, 2023
AuthorsTao 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 / Huawei Zhang /
PubMed AbstractClC-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- ...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.
External linksNat Commun / PubMed:37296152 / PubMed Central
MethodsEM (single particle)
Resolution3.5 Å
Structure data

34202

8gqu

EMDB-34202, PDB-8gqu:
AK-42 inhibitor binding human ClC-2 TMD
Method: EM (single particle) / Resolution: 3.5 Å

Chemicals

ChemComp-GH6:
2-[[2,6-bis(chloranyl)-3-phenylmethoxy-phenyl]amino]pyridine-3-carboxylic acid

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / homo-dimer

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