8GQU
AK-42 inhibitor binding human ClC-2 TMD
Summary for 8GQU
| Entry DOI | 10.2210/pdb8gqu/pdb |
| EMDB information | 34202 |
| Descriptor | Chloride channel protein 2, 2-[[2,6-bis(chloranyl)-3-phenylmethoxy-phenyl]amino]pyridine-3-carboxylic acid (2 entities in total) |
| Functional Keywords | homo-dimer, membrane protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 198063.17 |
| Authors | Wang, L. (deposition date: 2022-08-30, release date: 2023-07-05, Last modification date: 2024-05-08) |
| Primary citation | Ma, T.,Wang, L.,Chai, A.,Liu, C.,Cui, W.,Yuan, S.,Wing Ngor Au, S.,Sun, L.,Zhang, X.,Zhang, Z.,Lu, J.,Gao, Y.,Wang, P.,Li, Z.,Liang, Y.,Vogel, H.,Wang, Y.T.,Wang, D.,Yan, K.,Zhang, H. Cryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42. Nat Commun, 14:3424-3424, 2023 Cited by PubMed 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. PubMed: 37296152DOI: 10.1038/s41467-023-39218-6 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.5 Å) |
Structure validation
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