9BFJ

Cryo-EM structure of human CHT1 in the choline bound state

Summary for 9BFJ

• Entry DOI: 10.2210/pdb9bfj/pdb
• EMDB information: 44498
• Descriptor: High affinity choline transporter 1, CHOLINE ION, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: choline transporter, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 66689.24

Authors

Xue, J.,Jiang, Y. (deposition date: 2024-04-17, release date: 2024-11-06, Last modification date: 2025-06-04)

Primary citation

Xue, J.,Chen, H.,Wang, Y.,Jiang, Y.
Structural mechanisms of human sodium-coupled high-affinity choline transporter CHT1.
Cell Discov, 10:116-116, 2024

PubMed Abstract: Mammalian sodium-coupled high-affinity choline transporter CHT1 uptakes choline in cholinergic neurons for acetylcholine synthesis and plays a critical role in cholinergic neurotransmission. Here, we present the high-resolution cryo-EM structures of human CHT1 in apo, substrate- and ion-bound, hemicholinium-3-inhibited, and ML352-inhibited states. These structures represent three distinct conformational states, elucidating the structural basis of the CHT1-mediated choline uptake mechanism. Three ion-binding sites, two for Na and one for Cl, are unambiguously defined in the structures, demonstrating that both ions are indispensable cofactors for high-affinity choline-binding and are likely transported together with the substrate in a 2:1:1 stoichiometry. The two inhibitor-bound CHT1 structures reveal two distinct inhibitory mechanisms and provide a potential structural platform for designing therapeutic drugs to manipulate cholinergic neuron activity. Combined with the functional analysis, this study provides a comprehensive view of the structural mechanisms underlying substrate specificity, substrate/ion co-transport, and drug inhibition of a physiologically important symporter.

PubMed: 39587078
DOI: 10.1038/s41421-024-00731-7

Experimental method

ELECTRON MICROSCOPY (2.35 Å)