8ZQP

Human high-affinity choline transporter CHT1 bound to ML352 under NaCl condition, with sodium ion coordinated.

This is a non-PDB format compatible entry.

Summary for 8ZQP

• Entry DOI: 10.2210/pdb8zqp/pdb
• EMDB information: 60387
• Descriptor: High affinity choline transporter 1, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 4-methoxy-3-[(1-methylpiperidin-4-yl)oxy]-N-{[3-(propan-2-yl)-1,2-oxazol-5-yl]methyl}benzamide, ... (5 entities in total)
• Functional Keywords: transporter, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 64236.15

Authors

Qiu, Y.,Gao, Y.,Zhao, Y. (deposition date: 2024-06-03, release date: 2024-12-04, Last modification date: 2024-12-25)

Primary citation

Qiu, Y.,Gao, Y.,Bai, Q.,Zhao, Y.
Ion coupling and inhibitory mechanisms of the human presynaptic high-affinity choline transporter CHT1.
Structure, 2024

PubMed Abstract: In cholinergic neurons, choline is the precursor of the excitatory neurotransmitter acetylcholine (ACh), which plays a fundamental role in the brain. The high-affinity choline transporter, CHT1, mediates the efficient recycling of choline to facilitate ACh synthesis in the presynapse. Here, we report high-resolution cryoelectron microscopic (cryo-EM) structures of CHT1 in complex with the inhibitors HC-3 and ML352, the substrate choline, and a substrate-free state. Our structures show distinct binding modes of the inhibitors with different chemical structures, revealing their inhibition mechanisms. Additionally, we observed a chloride ion that directly interacts with the substrate choline, thereby stabilizing its binding with CHT1. Two sodium ions, Na2 and Na3, were clearly identified, which we speculate might be involved in substrate binding and conformational transitions, respectively. Our structures provide molecular insights into the coupling mechanism of ion binding with substrate binding and conformational transitions, promoting our understanding of the ion-coupled substrate transport mechanism.

PubMed: 39657660
DOI: 10.1016/j.str.2024.11.009

Experimental method

ELECTRON MICROSCOPY (3.1 Å)