ArticleNature communications2024
Structural basis of adenine nucleotides regulation and neurodegenerative pathology in ClC-3 exchanger.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Abnormal ClC-3/TMEM9-mediated endosomal ion transport in CLCN3-associated neurodevelopmental disease.EMBO molecular medicine · 2026Article
- Folding and Oligomerization of CLC Channels and Transporters.Chemical reviews · 2026Review
- Mitochondrial Dynamics and SLC25 Transporters in Neurodegeneration: From Mechanisms to Therapeutic Opportunities.Biomolecules · 2026Review
- Database ofKidney international reports · 2026Article
- Molecular Mechanisms of CLCN5 Missense Mutations in Dent Disease Type 1: A Comprehensive Computational Analysis and Clinical Correlations in a Chinese Cohort.Journal of cellular and molecular medicine · 2026Article
- Molecular mechanism of exchange coupling in CLC chloride/proton antiporters.Nature communications · 2026Article
- ClC-3 mediates angiotensin II-induced endothelial dysfunction by inhibiting Akt-Hsp90-eNOS signaling pathway.Frontiers in pharmacology · 2026Article
- Structural basis of ClC-3 transporter inhibition by TMEM9 and PtdIns(3,5)PNature structural & molecular biology · 2025Article
- Endosomal chloride/proton exchangers need inhibitory TMEM9 β-subunits for regulation and prevention of disease-causing overactivity.Nature communications · 2025Article
- ALLIN: A tool for annotation of a protein alignment combined with structural visualization.The Journal of general physiology · 2025Article
Corrections and comments
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Authors and funding
14 authors.
Funding
Abstract
The ClC-3 chloride/proton exchanger is both physiologically and pathologically critical, as it is potentiated by ATP to detect metabolic energy level and point mutations in ClC-3 lead to severe neurodegenerative diseases in human. However, why this exchanger is differentially modulated by ATP, ADP or AMP and how mutations caused gain-of-function remains largely unknow. Here we determine the high-resolution structures of dimeric wildtype ClC-3 in the apo state and in complex with ATP, ADP and AMP, and the disease-causing I607T mutant in the apo and ATP-bounded state by cryo-electron microscopy. In combination with patch-clamp recordings and molecular dynamic simulations, we reveal how the adenine nucleotides binds to ClC-3 and changes in ion occupancy between apo and ATP-bounded state. We further observe I607T mutation induced conformational changes and augments in current. Therefore, our study not only lays the structural basis of adenine nucleotides regulation in ClC-3, but also clearly indicates the target region for drug discovery against ClC-3 mediated neurodegenerative diseases.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.