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TitleIon coupling and inhibitory mechanisms of the human presynaptic high-affinity choline transporter CHT1.
Journal, issue, pagesStructure, Year 2024
Publish dateNov 26, 2024
AuthorsYunlong Qiu / Yiwei Gao / Qinru Bai / Yan Zhao /
PubMed AbstractIn 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, ...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.
External linksStructure / PubMed:39657660
MethodsEM (single particle)
Resolution2.5 - 3.6 Å
Structure data

60386

8zqo

EMDB-60386, PDB-8zqo:
Human high-affinity choline transporter CHT1 bound to HC-3 under NaCl condition, with sodium and chloride ions coordinated.
Method: EM (single particle) / Resolution: 2.8 Å

60387

8zqp

EMDB-60387, PDB-8zqp:
Human high-affinity choline transporter CHT1 bound to ML352 under NaCl condition, with sodium ion coordinated.
Method: EM (single particle) / Resolution: 3.1 Å

60388

8zqq

EMDB-60388, PDB-8zqq:
Human high-affinity choline transporter CHT1 bound to choline under NaCl condition, with sodium and chloride ions coordinated.
Method: EM (single particle) / Resolution: 2.5 Å

60389

8zqr

EMDB-60389, PDB-8zqr:
Human high-affinity choline transporter CHT1 in apo state under NaCl condition.
Method: EM (single particle) / Resolution: 3.6 Å

Chemicals

ChemComp-NA:
Unknown entry

ChemComp-HC6:
(2S,2'S)-2,2'-biphenyl-4,4'-diylbis(2-hydroxy-4,4-dimethylmorpholin-4-ium)

ChemComp-CL:
Unknown entry

ChemComp-HOH:
WATER

PDB-1aow:
ANNEXIN IV

ChemComp-CHT:
CHOLINE ION

Source
  • homo sapiens (human)
KeywordsSTRUCTURAL PROTEIN / transporter / TRANSPORT PROTEIN

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