8gqu
From Proteopedia
AK-42 inhibitor binding human ClC-2 TMD
Structural highlights
DiseaseCLCN2_HUMAN Leukoencephalopathy with mild cerebellar ataxia and white matter edema;Familial hyperaldosteronism type II;Juvenile myoclonic epilepsy. Disease susceptibility is associated with variants affecting the gene represented in this entry. Disease susceptibility may be associated with variants affecting the gene represented in this entry. Disease susceptibility is associated with variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. FunctionCLCN2_HUMAN Voltage-gated chloride channel. Chloride channels have several functions including the regulation of cell volume, membrane potential stabilization, signal transduction and transepithelial transport. Involved in the regulation of aldosterone production. The opening of CLCN2 channels at hyperpolarized membrane potentials in the glomerulosa causes cell membrane depolarization, activation of voltage-gated Ca2+ channels and increased expression of aldosterone synthase, the rate-limiting enzyme for aldosterone biosynthesis (PubMed:29403011, PubMed:29403012).[1] [2] [3] [4] Publication Abstract from PubMedClC-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 A 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. Cryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42.,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 YT, Wang D, Yan K, Zhang H Nat Commun. 2023 Jun 9;14(1):3424. doi: 10.1038/s41467-023-39218-6. PMID:37296152[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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