9BIM

Cryo-EM structure of human CHT1 in the HC-3 bound outward-facing state

Summary for 9BIM

• Entry DOI: 10.2210/pdb9bim/pdb
• EMDB information: 44593
• Descriptor: High affinity choline transporter 1, (2S,2'S)-2,2'-biphenyl-4,4'-diylbis(2-hydroxy-4,4-dimethylmorpholin-4-ium) (2 entities in total)
• Functional Keywords: choline transporter, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 66941.16

Authors

Xue, J.,Jiang, Y. (deposition date: 2024-04-23, release date: 2024-11-06, Last modification date: 2025-05-14)

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 (3.67 Å)