8JGV

Cryo-EM structure of mClC-3_I607T with ATP

Summary for 8JGV

• Entry DOI: 10.2210/pdb8jgv/pdb
• EMDB information: 36246
• Descriptor: H(+)/Cl(-) exchange transporter 3, ADENOSINE-5'-TRIPHOSPHATE (2 entities in total)
• Functional Keywords: membrane protein
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 2
• Total formula weight: 182905.89

Authors

Wan, Y.Z.Q.,Yang, F. (deposition date: 2023-05-21, release date: 2024-09-04, Last modification date: 2024-10-30)

Primary citation

Wan, Y.,Guo, S.,Zhen, W.,Xu, L.,Chen, X.,Liu, F.,Shen, Y.,Liu, S.,Hu, L.,Wang, X.,Ye, F.,Wang, Q.,Wen, H.,Yang, F.
Structural basis of adenine nucleotides regulation and neurodegenerative pathology in ClC-3 exchanger.
Nat Commun, 15:6654-6654, 2024

PubMed 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.

PubMed: 39107281
DOI: 10.1038/s41467-024-50975-w

Experimental method

ELECTRON MICROSCOPY (2.98 Å)